Mitochondrion 16 (2014) 7–17

Contents lists available at ScienceDirect

Mitochondrion
journal homepage: www.elsevier.com/locate/mito

Metabolic features of the cell danger response☆

Robert K. Naviaux ⁎
The Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, and Pathology, University of California, San Diego School of Medicine,
214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467, USA
Veterans Affairs Center for Excellence in Stress and Mental Health (CESAMH), La Jolla, CA, USA

a r t i c l e i n f o a b s t r a c t

Available online 24 August 2013 The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts
from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular ca-
Keywords: pacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity
Oxidative stress produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dy-
Oxidative shielding namics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability,
Innate immunity
metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of
Inflammation
Purinergic signaling
danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates,
Mitochondria oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been
eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activat-
ed to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut
microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed,
and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mito-
chondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a
process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic
life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordi-
nated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem
and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An under-
standing of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmen-
tal, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD),
attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensi-
tivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress
disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal
ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson dis-
ease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing
cholangitis.
© 2013 The Author. Published by Elsevier B.V. and Mitochondria Research Society. All rights reserved.

1. Introduction that is activated when a cell encounters a chemical, physical, or micro-

bial threat that could injure or kill the cell. Common microbial threats
Cells have a limited number of ways they can respond to threat. An are viruses, bacteria, fungi, and parasites. Physical threats include heat,
important consequence of this is that evolutionary selection preserves salt, or pH shock, or UV or ionizing radiation. Chemical forms of danger
similar cellular responses to diverse forms of threat. The cell danger re- include heavy and trace metals like lead, mercury, cadmium, arsenic,
sponse (CDR) is an evolutionarily conserved cellular metabolic response and nickel, certain electrophilic aromatic chemicals like the plasticizer
bisphenol A, the chemical flame retardants like the brominated
diphenyl ethers (BDEs), and certain halogenated pesticides like chlor-
pyrifos and DDT. Psychological trauma, particularly during childhood,
☆ This is an open-access article distributed under the terms of the Creative Commons can also activate the cell danger response, produce chronic inflamma-
Attribution-NonCommercial-No Derivative Works License, which permits non-commercial tion, and increase the risk of many disorders (Ehlert, 2013). Mixtures
use, distribution, and reproduction in any medium, provided the original author and source of these factors and susceptible genotypes have synergistic effects. The
are credited. total load of triggers is integrated by metabolism and regulates the
⁎ The Mitochondrial and Metabolic Disease Center, University of California, San Diego
School of Medicine, 214 Dickinson St., Bldg CTF, Rm C102, San Diego, CA 92103-8467,
CDR. Mitochondria are evolved to sense all of these threats according
USA. Tel.: +1 619 543 2105; fax: +1 619 543 7868. to the induced changes in electron flow available for normal metabo-
E-mail address: [email protected]. lism. This review will emphasize communication between mitochondria

1567-7249/$ – see front matter © 2013 The Author. Published by Elsevier B.V. and Mitochondria Research Society. All rights reserved.
http://dx.doi.org/10.1016/j.mito.2013.08.006
8 R.K. Naviaux / Mitochondrion 16 (2014) 7–17

and the nucleus, and show how many pathways of extracellular, cell– disturbances produce these syndromes is well established, no unifying
cell communication are ultimately traceable to mitochondrial metabo- mechanistic theory exists to explain the development of these complex
lism. The cell danger response is coordinated in the brain via neuroimmuno-developmental disorders.
chemosensory integration of whole body and microbiome metabolism.
Abnormal persistence of the CDR ultimately leads to altered organ func-
tion and behavior, and results in chronic disease. 2.2. Purinergic signaling
Small molecule nutrients and metabolites are the prime movers of
the CDR. Protein, glycan, RNA, epigenetic, and genetic changes are es- Purinergic signaling was pioneered by Geoffrey Burnstock in the
sential, but secondary, and can only be understood with reference to early 1970s, when he described the first examples of non-adrenergic,
the prime drivers in metabolism. Readers interested in the mitochon- non-cholinergic (NANC) signaling mediated by the stimulated release
dria-associated proteins (Arnoult et al., 2011), glycans (Angata et al., of ATP (Burnstock et al., 1972). Skepticism was high in the early days
2012), microRNAs, genetics, and epigenetics (Knight, 2013) of innate that extracellular ATP could actually be a neurotransmitter. With the
immunity and inflammation that are associated with the CDR are re- cloning of 19 different purinergic receptors that are widely distributed
ferred to recent reviews on those topics. in every neural and non-neural tissue of the body, this early skepticism
has been soundly extinguished (Burnstock and Verkhratsky, 2009;
2. Historical foundations Burnstock et al., 2010, 2011). Today, the role of purinergic signaling con-
tinues to expand virtually into every fundamental cell communication,
The concept of the cell danger response described in this review stress response, autonomic, vestibular, and sensory integration pathway
has evolved from a confluence of six rivers of scholarship that have known (Bours et al., 2011; Burnstock, 2012; Choo et al., 2013; Halassa,
developed in relative isolation over the past 60 years. Briefly these 2011; Junger, 2011; Pimentel et al., 2013).
are: 1) the recognition that inherited disorders in purine and pyrimidine
metabolism produce distinct behavioral and immunologic phenotypes
that are not explained by current concepts in neuropharmacology and 2.3. Immunologic cell danger
immunology, 2) the recognition that extracellular purines and pyrimi-
dines like ATP, ADP, UTP, and UDP bind to ubiquitous ion channels Polly Matzinger and Ephraim Fuchs developed the cell danger model
and G-protein coupled receptors (GPCRs) to control everything from of tolerance and immunoreactivity in the early 1990s to explain why ef-
neurotransmission, to cortisol production, inflammation, chronic pain fective adaptive immune responses are best mounted under conditions
signaling, and control of the autonomic nervous system, 3) the recogni- of cell danger and injury (Dreifus, 1998; Matzinger, 1994). This danger
tion that immunologic systems have evolved not to distinguish self from theory of immunology has produced many fruitful insights over the
non-self, but rather to respond to threats that result in cellular injury, past 20 years ranging from contributions to tumor immunology, to
4) the recognition from the field of virology that the most adaptive graft versus host disease, allergy, asthma, and next generation adjuvants
strategy is a co-evolutionary negotiation between virus and host, that (Fuchs and Matzinger, 1996; Matzinger and Kamala, 2011; Seong and
the pre-exposure condition of the host determines a large fraction of Matzinger, 2004).
the pathology of infection, and that across virtually all classes of animal
cell viruses studied, considerable genetic reserves are expended to tar-
2.4. Virology
get the host mitochondrial “danger alarm system”, 5) the recognition
within the field of mitochondrial medicine of that extracellular nucleo-
Since the polio epidemics of the 1950s, we've learned that the vast
tides are ultimately traceable to mitochondria and that one of the
majority of infections do not kill or permanently disable the host. In
most ancient functions of mitochondria is cellular defense—the detec-
the case of polio, just 1 in 150 to 1 in 1800 people infected develops par-
tion and response to cellular danger as a fundamental component of
alytic disease (Nathanson and Kew, 2010). More than 99% of poliovirus
innate immunity, and 6) the concept that humans and all other animals
infections are either silent, or lead to self-limited upper respiratory tract
are ecosystems of cooperating cells, and that even the most complex
infections (“colds”), or flu-like abdominal symptoms. Malnutrition and
ecosystems on Earth can be understood and made more resilient with
innate immune status are major factors that determine the probability
attention to the relevant forcing variables of physical habitat, resource
that exposure to poliovirus will result in paralytic disease. Darwin
availability, complementary biodiversity, elimination of invasive spe-
went further. He recognized that many indigenous people were ravaged
cies, and the recycling and removal of metabolic end products.
by disease that was brought by European explorers aboard ships where
no disease was evident. Native people had an innate susceptibility to
2.1. Biochemical genetics
disease that did not affect the European explorers. He noted this phe-
nomenon during his visit to Australia in 1836:
Biochemical genetics is a mature medical subspecialty that dates to
the publication of Sir Archibald Garrod's report of the Mendelian inher- It is certainly a fact, which cannot be controverted, that most of the dis-
itance of alkaptonuria in 1902 (Garrod, 1902), and has been dedicated eases that have raged in the islands during my residence there, have
to the care of children and adults with inborn errors of metabolism been introduced by ships; and what renders this fact remarkable is that
since the 1960s. William Nyhan is one of the fathers of the field of bio- there might be no appearance of the disease among the crew of the ship
chemical genetics and a mentor to many leaders in the field today. which conveyed this destructive importation (Darwin, 1839).
Dr. Nyhan published the first example of an inherited defect in
purine metabolism that profoundly altered behavior known as Lesch– The comprehensive study of viral gene structure since the 1990s has
Nyhan Disease (Lesch and Nyhan, 1964). Just a few years later he revealed that virtually every class of animal virus has incorporated into
published the first example of a child with autism-like behaviors its genome the machinery to thwart, suppress, neutralize, or evade the
resulting from an inherited increase in purine synthesis known as mitochondrial “danger alarm system” (Corcoran et al., 2009; Ohta and
phosphoribosylpyrophosphate synthase (PRPPS) super activity syn- Nishiyama, 2011; Scott, 2010). This genetic insight has cast a bright
drome (Nyhan et al., 1969). Both disorders resulted in a profound in- light on the role of mitochondria in antiviral signaling, and cellular de-
crease in de novo purine biosynthesis. The complex behavioral and fense. In this review, the role of mitochondria in the initiation and main-
immunologic syndromes produced by inherited defects in purine and tenance of the cell danger response is placed in context of coordinated
pyrimidine metabolism have recently been reviewed (Micheli et al., changes in whole cell, and whole body metabolism, that together lead
2011; Nyhan, 2005). Although the fact that purine and pyrimidine to changes in neurodevelopment, behavior, and to chronic disease.
 R.K. Naviaux / Mitochondrion 16 (2014) 7–17 9

2.5. Mitochondrial medicine mass spectrometry and metabolomics methods in each complex disease
state, before and after successful treatment.
For many years, the treatment of inborn errors in mitochondrial In ecology, an ecosystem can fail or become unhealthy for many rea-
oxidative phosphorylation was directed at trying to restore cellular sons. The field of restoration ecology concerns itself both with identify-
ATP production, with limited success. At one memorable meeting in ing the governing dynamics of the complex system, and with the
Melbourne, Australia in 1998, the distinguished yeast geneticist, bio- identification of the discrete factors that can be modified to restore
chemist, and mitochondrial biologist Dr. Anthony Linnane stood up health and resilience to the system (Gunderson, 2000). The same is
and commented (to paraphrase), “If we are intellectually honest, we true in medicine. An important forcing variable in the control of chronic
must discard old ideas and look for new paradigms to explain the inflammation and the cell danger response is purinergic signaling.
cause of symptoms in a disease if we test a rationally designed therapy
in patients with the disease, but it fails repeatedly.” Mitochondria are lo- 3. The cell danger response
cated at the hub of the wheel of metabolism, contain 1500 proteins tai-
lored to meet the needs of each different cell type, and catalyze over 500 When ATP synthesis, nucleotide metabolism, and associated
different chemical reactions in metabolism. The connection between purinergic signaling are disturbed, a coordinated set of cellular re-
neurodegenerative episodes and infection in mitochondrial disease sponses is triggered that evolved to help the cell defend itself from mi-
was recognized and quantified in the early 2000s (Edmonds et al., crobial attack or physical harm. Elements of this cell danger response
2002). With the discovery that mitochondria represented the front (CDR) have been given many names that reflect the level and tools of
lines in cellular defense and innate immunity, this connection between analysis used to study it. The CDR includes the endoplasmic reticulum
neurological setbacks and infection began to be understood (Seth et al., (ER) stress response (Liu et al., 2008), the unfolded protein response
2005; West et al., 2011). Ultimately, all the phosphorylated nucleotides (Lee and Glimcher, 2009), the mitochondrial unfolded protein response
of the cell are traceable to reactions in mitochondria. This makes mito- (Haynes et al., 2013), the heat shock protein response (Kim et al., 2006),
chondria fundamental sources of nucleotides for purinergic signaling. the integrated cell stress response (Silva et al., 2009), the oxidative
stress response (Lushchak, 2010), the oxidative shielding response
(Naviaux, 2012), innate immunity (West et al., 2011), and inflammation
2.6. Ecology and medicine (Zhou et al., 2011). These can be understood as a unified, and function-
ally coordinated response by considering the CDR in its most fundamen-
Even the most complex ecosystem dynamics can be understood as a tal and most ancient role; to improve cell and host survival after viral
function of a discrete set of forcing variables that include the physical attack. The acute CDR produces at least 8 functional changes: 1) it shifts
habitat, resources, complementary biodiversity, disruptive biodiversity cellular metabolism from net polymer synthesis to monomer synthesis
(invasive species), and the recycling and removal of metabolic end to prevent the hijacking and assembly of cellular resources by intracel-
products. Metabolism, and indeed, whole body function and develop- lular pathogens, 2) it stiffens the membranes of the cell and circum-
ment can be considered as a complex web of interconnected and scribes an area of damage to limit pathogen egress, 3) releases
interdependent pathways that change in an orderly pattern from con- antiviral and antimicrobial chemicals into the pericellular environment,
ception to old age. Ecologists focus on the identification of drivers, forc- 4) increases autophagy and mitochondrial fission to remove intracellu-
ing variables, or state variables that can alter the state of an ecosystem, lar pathogens, 5) changes DNA methylation and histone modification to
preserve resilience, or drive succession. Drivers are discrete physical, alter gene expression, 6) mobilizes endogenous retroviruses and other
chemical, or biological entities that when changed a small amount, pro- mobile genetic elements like the long interspersed nuclear elements
duce large changes in the interaction and performance of the ecosystem (LINEs) to produce genetic variations, 7) warns neighboring cells and
as a whole. For example, factors like sunlight, ocean temperature, pH, distant effector cells of the danger, and 8) alters the behavior of the
CO2, and dissolved oxygen concentration produce dramatic changes in host to prevent the spread of infection to kin and sleep patterns to facil-
the health of coral reef ecosystems (Riegl et al., 2009). itate healing (Fig. 1).
As we reduce the scale of analysis to the level of the cell, the details of
chemistry become more important, and the time constants of response 3.1. Ancient and modern triggers of the CDR
shorten from years in terrestrial ecosystems, to seconds to months
in metabolism. Physical habitats are established in complementary mi- In the Precambrian seas, the only cells that could transmit their DNA
crohabitats in each organ, like interdependent structures in the brain. to the next generation were cells that had successfully survived infec-
Species become differentiated cell types in tissues that develop tion by viruses and other microbial pathogens, and exposure to a wide
complementary and interdependent metabolisms. Within a cell, spe- array of chemical and physical forces that were fixtures of the young
cialized proteins and enzymes are organized in complementary and biosphere. Early cells synthesized ATP and other nucleotides for a di-
interdependent compartments or microhabitats called organelles, and verse array of metabolic functions in addition to RNA and DNA synthe-
trophic layers in a network. These intracellular trophic layers distin- sis. The concentration of ATP inside of single cells is typically about
guish proteins needed for the recycling of nutrients, from proteins re- 1–5 mM—nearly one million times more than in the extracellular envi-
quired for the synthesis of secondary metabolites and polymers— ronment (b5–10 nM). When a cell was injured or lysed by a virus, ATP
larger structures from smaller building blocks. Resources in the cell and other nucleotides and metabolites were released into the surround-
are the chemical building blocks of proteins, fats, carbohydrates, and ing area, creating a bright chemical “flare” warning other cells of the
nucleic acids. More generally, the traffic flow patterns of resources and danger and the presence of a pathogen.
electrons within a cell determine its state of health, alarm, or disease. Before a cell is broken or lysed, mitochondria in an infected eukary-
What are the state variables in metabolism? In metabolism, pH, CO2, otic cell sense the presence of an intruding microbe by detecting the
and oxygen are also important state variables. However, metabolic in- diversion of electrons (as NADH and NADPH) and carbon to viral bio-
termediates like alpha-ketoglutarate (AKG), and cofactors and vitamins genesis centers for polymer synthesis to make viral RNA, protein, and
are also state variables. Deficiencies in vitamin C produce defects in DNA from building blocks in the host cell. This “electron steal” is sensed
collagen proline hydroxylation and neurotransmitter metabolism as a voltage drop, or decrease in electron flow available within the cell
known as scurvy. Deficiencies in thiamine produce defects in glucose, for oxidative phosphorylation in mitochondria. The metabolic conse-
pyruvate, and amino acid metabolism that cause Beriberi and quences are nearly instantaneous. Mitochondria rapidly decrease their
Wernicke–Korsakoff syndrome. Other drivers or state variables in me- oxygen consumption, which is coupled to electron flow. The dissolved
tabolism will be discovered by the systematic application of advanced oxygen concentration in the cell begins to rise because mitochondria
10 R.K. Naviaux / Mitochondrion 16 (2014) 7–17

with and disrupts normal metabolic or hormone signaling. Mixtures of

chemical and biological threats can have synergistic effects, and the
total load of danger triggers can influence the magnitude and form of
the CDR. When danger is detected, mitochondria alter cellular metabo-
lism to help shield the cell from further injury. This is accomplished by
stiffening cell membranes, activating the production of reactive oxygen
species (ROS), and producing changes in many different pathways in
intermediary metabolism that have the effect of limiting pathogen rep-
lication and limiting the spread of danger (Naviaux, 2012). These path-
ways are immature in newborns and growing children (Wood et al.,
2010), leading to effects that are not limited to inflammation and innate
immunity in peripheral tissues, but can also alter neurodevelopment
(Landrigan et al., 2012) and increase the risk of other chronic childhood
diseases.

3.2. Summer and winter metabolism

Large trends in the seasonal variation of metabolism can be placed in

context by considering the evolutionary forces that have acted on our
ancestors. Seasonal changes in calorie availability were the rule. Sum-
mer was a time of plenty, when the environment provided abundant
calories, which were harvested with physical exercise. This was a natu-
ral time for cell growth, during which building blocks were polymerized
to produce new cells and increase biomass. Physical exercise ensured
that the added biomass was functionally efficient. The master fuel
sensor in the cell during summer is mTOR (mammalian target of
Fig. 1. Functions of the acute cell danger response. The acute CDR includes 8 functional rapamycin) (Yang and Ming, 2012). mTOR facilitates protein synthesis
changes in cell structure, physiology, metabolism, and gene expression. These are: and growth using new materials taken in from the environment.
1) shift cellular metabolism from polymer to monomer synthesis to prevent the hijacking mTOR inhibits the internal recycling of used or damaged cellular re-
and assembly of cellular resources by intracellular pathogens, 2) stiffen the cell mem-
sources by autophagy. The pathways supported by mTOR are Janus
branes to limit superinfection and pathogen egress, 3) release antiviral and antimicrobial
chemicals into the pericellular environment, 4) increase autophagy, mitochondrial fission, faced. In cells capable of dividing, mTOR promotes rapid growth with
and mitophagy to facilitate removal of intracellular pathogens and biogenesis centers, net polymer synthesis, without inflammation. Used or damaged pro-
5) change DNA methylation and histone modification to alter gene expression, 6) mobilize teins, lipids, glycans, RNA, and DNA are diluted by new synthesis
endogenous retroviruses and LINEs to produce genetic variations, 7) warn neighboring
from fresh building blocks obtained from rich summer ecosystems.
cells and distant effector cells of the danger with extracellular nucleotides, H2O2, eicosa-
noids, metabolites, and cytokines, and 8) alter the behavior of the host to prevent the In differentiated cells that cannot dispose of excess calories without
spread of infection to kin, and sleep patterns to facilitate healing. Abbreviations: HSPs: hypertrophy, mTOR excess results in the accumulation of old and
heat shock proteins; AMPs: antimicrobial peptides; D-cells: Dendritic Cells; ERVs: endog- damaged macromolecules like oxidized or aggregated proteins, and
enous retroviruses; LINEs: long interspersed nuclear elements; meDNA: methylated DNA; produces chronic inflammation—oxidizing conditions that act as a
dNTPs: deoxynucleoside triphosphates; CNS: central nervous system.
thermodynamic break on the inexorable accumulation of intracellular
polymers like lipids, proteins, glycogen, and nucleic acids from their
monomer building blocks.
are the oxygen sink in every eukaryotic cell. This makes the cellular Winter was a time of caloric restriction and a time when resources
redox chemistry more oxidizing (Naviaux, 2012). Highly oxidizing envi- stored in the summer and fall had to be used with great efficiency if sur-
ronments strongly inhibit the assembly of monomeric building blocks vival was to be assured. The master fuel sensor in the winter is AMPK
into polymers, and rapidly decrease the efficiency of RNA, protein, and (AMP activated protein kinase) (Salminen and Kaarniranta, 2012).
DNA synthesis by the infecting virus. Oxidizing conditions also result AMPK optimizes energy efficiency and stimulates the recycling of cellu-
in the oxidation of sulfur in methionine, and thiols like cysteine, homo- lar materials in autophagy. This cycle occurs to a lesser extent each night
cysteine, and glutathione, and the disassembly of iron–sulfur clusters in and during fasting. The pathways activated by AMPK support regenera-
many enzyme systems, and decrease the availability of the thiol of coen- tion and are anti-inflammatory because they work to break down
zyme A that is essential for intermediary metabolism. damaged proteins, lipids, glycans, RNA, and DNA. AMPK facilitates the
The ability of mitochondria to monitor electron flow and sulfur oxi- resynthesis of these macromolecules from newly synthesized mono-
dation makes them ideally suited as generalized cell “danger alarms”. mers and refreshed building blocks. Monomer synthesis and polymer
Their rapid metabolism makes mitochondria the “canaries in the coal synthesis are balanced for winter maintenance. Historically, before the
mine” for the cell. Any trace or heavy metal that acts as an electrophile 1980s, most human nutrition research was focused on disorders of de-
or sulfurophile in the cell will trigger a mitochondrial response that ficiency. After the 1980s, much of human nutrition research has been
is similar to that of a viral infection, because metal electrophiles and rep- redirected to disorders of caloric excess. Indeed many of the genes
licating pathogens both divert and consume electrons. Likewise, a large that have been found to guard against age-related diseases like diabetes,
number of molecules have been synthesized since the 1850s as dyes, cancer, and heart disease are found to be “winter genes” coordinated by
pesticides, drugs, and industrial chemicals. Many are polyaromatic and AMPK, while the “summer genes” coordinated by mTOR lead to chronic
halogenated. These modern chemicals with conjugated ring systems, disease and inflammation when combined with caloric excess and
multiple double bonds, and delocalized π orbital electron clouds are physical inactivity. Technological progress and industrial scale farming
highly electrophilic and will produce an electron steal within the cell practices have been a double-edge sword for the health of populations
that can also activate the CDR. The CDR is a generic, but highly evolved around the world. Many developed nations now experience an “endless
response that often complicates more specific molecular effects that summer” of calorie availability, decreased physical exercise, and an ab-
occur when a synthetic molecule binds to a receptor, or competes sence of the historical norm of winter caloric restriction. This has led to
 R.K. Naviaux / Mitochondrion 16 (2014) 7–17 11

modern epidemics of obesity in both adults and children, and to a grow- synthesis and release from the adrenal cortex, independent of ACTH
ing tide of chronic disease traceable to cellular inflammation. stimulation (Kawamura et al., 1991).

4. Metabolic features of the CDR 4.4. Cysteine and sulfur

The following section is designed to be read with close reference to Sulfur metabolism is shifted such that glutathione is consumed in
Fig. 2. Panels A and B illustrate 21 branch points in metabolism that glutathionylation regulatory (McLain et al., 2013) and liver phase II de-
are normally tipped in the direction of “healthy development”, reducing toxification reactions (Zamek-Gliszczynski et al., 2006), and cysteine is
conditions, polymer synthesis and renewal (upward in the figure). diverted to H2S, taurine, and sulfate excretion (Stipanuk and Ueki,
However, when a cell is infected by a virus or other microbial pathogen, 2011). As an important compensation, the increased plasma oxidation
metabolism is shifted to innate immunity, inflammation, oxidizing con- state of the CDR favors cysteine oxidation to cystine (CySSCy), which
ditions, and monomer synthesis to oppose the efforts of the pathogen to is used to transport needed cysteine across the blood–brain barrier to
parasitize resources and replicate itself by assembling polymers. The the brain (Bridges et al., 2012; Lewerenz et al., 2013), and into macro-
shift in metabolism during this cell danger response (CDR) is indicated phages for glutathione synthesis (Kobayashi et al., 2012).
in the downward direction in the Figure. When these changes occur in
the context of cell division and the distribution of accumulated biomass 4.5. Vitamin D
to daughter cells during growth, then inflammation is avoided unless
accompanied by significant cell damage. Problems arise when these In the face of normal body stores of calcium and phosphorus, vitamin
conditions are activated in post-mitotic tissues that have a limited ca- D metabolism is altered significantly by the CDR. A mitochondrial P450
pacity for growth. The list of metabolic branch points in Fig. 2AB is not enzyme, the 1α hydroxylase, in the kidney is required to activate 25-
intended to be comprehensive, and not all metabolic fates of the Hydroxyvitamin D to hormonally active, 1,25-Dihydroxyvitamin D.
branch-point metabolites are discussed. The reader is referred to topical Another mitochondrial enzyme, the 24α-hydroxylase, is used to inacti-
reviews of each of the branch point metabolites of interest for more vate vitamin D. The 24α-hydroxylase is increased by cell danger threats
comprehensive discussion. like endotoxin (Shanmugasundaram and Selvaraj, 2012). This decreases
the concentration of active vitamin D and contributes to the CDR by in-
4.1. Mitochondria creasing inflammation, but also increases the risk of developing of auto-
antibodies that may include anti-thyroid antibodies (Kivity et al., 2011),
Mitochondria fragment under conditions of the CDR leading to inef- and may contribute to the development of other autoantibodies like
fective control and propagation of intracellular calcium transients anti-folate receptor antibodies.
(Eisner et al., 2010). When cells are injured and mitochondrial proteins
are released to the extracellular space, formyl-methionine initiated mi- 4.6. Folate and B12 metabolism
tochondrial proteins can stimulate inflammation via the formyl-peptide
receptor (Rabiet et al., 2005). Extracellular mitochondrial DNA activates The metabolism of folic acid and vitamin B12 is tightly inter-
innate immunity via the TLR9 receptor (West et al., 2011), and is specif- connected with mitochondrial function, sulfur metabolism, glycine, ser-
ically released during infection by eosinophils as an antimicrobial net ine, nucleotide synthesis, and DNA and histone methylation (Naviaux,
(Yousefi et al., 2008). 2008). Out of over 2700 enzymes encoded by the human genome
(Romero et al., 2005) only two require B12, but no fewer than 15 pro-
4.2. Oxygen teins are dedicated to the absorption, transport, and metabolism of
B12 (Nielsen et al., 2012). One of the two enzymes is methylmalonyl
When mitochondrial oxygen consumption decrease, dissolve cyto- CoA mutase. It is located in mitochondria and uses the adenosyl form
plasmic oxygen rises and activates reactive oxygen species (ROS) pro- of B12, adenosylcobalamin to convert methylmalonyl-CoA to succinyl-
duction by many enzyme systems including NOX4 (Hecker et al., CoA for import into the Krebs cycle. The other B12-dependent enzyme,
2009). Increased dissolved oxygen, superoxide and hydrogen peroxide methionine synthase (MS), is located in the cytosol and uses the methyl
activate many proteins including the central inflammatory regulator form of B12, methylcobalamin, to synthesize methionine from homo-
NFkB (Lluis et al., 2007) and the multifunctional transglutaminase 2 cysteine. Methionine can be used to initiate protein synthesis, or as a
(Caccamo et al., 2012). Although ROS are sometimes considered intrin- precursor for S-adenosyl methionine (SAM) synthesis. Ultimately the
sically inflammatory, it is interesting to note that one of the most de- flux through alternative pathways of folate, glutathione, and methio-
structive genetic forms of chronic inflammatory disease is one that nine metabolism is determined by cellular redox poise. Under oxidizing
cannot produce ROS in response to infection. Chronic granulomatous conditions of the CDR, SAM is directed preferentially to polyamine
disease (CGD) is caused by the genetic deficiency of subunits of synthesis to assist with ROS and antiviral and antimicrobial polyamine
phagocyte NADPH oxidase 2 (NOX2) that makes the child unable to aldehyde synthesis and release (Bachrach, 2007). This lowers the
produce significant amounts of superoxide, hydrogen peroxide, and SAM/SAH ratio, while simultaneously decreasing net availability of
hypochlorous acid for antibacterial and antifungal defense (Kuijpers SAM for DNA methylation reactions. Gene- and cell type-specific de-
and Lutter, 2012). In another example, ROS are protective, and now rec- methylation of histones is stimulated by oxidizing conditions of the
ognized as important inhibitors of inflammation in autoimmune disor- CDR by the Jumonji histone demethylases, increasing expression of
ders like rheumatoid arthritis, multiple sclerosis, thyroiditis, and type pro-inflammatory cytokines like TNFα (Kruidenier et al., 2012). In
1 diabetes (Hultqvist et al., 2009). addition, the oxidizing conditions of the CDR increase the ratio of
formyl-tetrahydrofolate to methyl-tetrahydrofolate (fTHF/mTHF) and
4.3. ATP the ratio of methylene-THF to mTHF. This favors the de novo synthesis
of nucleotides like IMP and dTMP that require 1-carbon donation from
Purinergic signaling nucleotides like ATP, ADP, UTP, and UDP are re- fTHR and methylene-THF, respectively. The resulting increase in IMP
leased in increased amounts from cells under stress and activate inflam- synthesis can be used to make purine nucleotides like ATP for purinergic
mation (Xia et al., 2012). Cells need not be broken or lysed to increase signaling. The oxidizing conditions of the CDR ensure that the resulting
the release of ATP, other nucleotides, and metabolites. ATP and sodium nucleotides will be used preferentially as monomers for metabolic and
urate crystals are activators of NLRP3 inflammasome assembly (Riteau signaling purposes, since assembly into polymers of RNA and DNA is
et al., 2012). Purinergic signaling via ATP directly stimulates cortisol chemically unfavorable.
12 R.K. Naviaux / Mitochondrion 16 (2014) 7–17

4.7. SAM decarboxylation by SAM decarboxylase, dcSAM is used as an essential

aminopropyl donor for polyamine and methylthioadenosine (MTA)
S-adenosyl methionine (SAM) is used as a universal methyl donor synthesis (Fontecave et al., 2004). When the CDR is activated, a larger
for DNA, histone, and neurotransmitter methylation reactions. After portion of SAM is diverted to the synthesis of polyamines like
 R.K. Naviaux / Mitochondrion 16 (2014) 7–17 13

spermidine and spermine, which can be used to synthesize hydrogen 4.12. Phospholipids
peroxide and potent antimicrobial aldehydes like 3-aminopropanal,
and 3-acetoaminopropanal (Cervelli et al., 2012). SAM can be usurped The membranes of all eukaryotic cells are composed largely of phos-
by invading pathogens as a methyl donor for the maturation of pholipids. Most of these are phosphoglycerolipids that are comprised of
pathogen mRNAs. S-adenosylhomocysteine (SAH) is a potent feedback a glycerol backbone, two fatty acid side chains, and a phosphate-
inhibitor of SAM-mediated methylation reactions. By decreasing the containing polar head group. The fluidity of the cell membrane is a bio-
SAM/SAH ratio, the CDR further consolidates an intracellular environ- physical consequence of thermal packing of the fatty acid side chains. In
ment that is unfavorable for pathogen replication. Adenosine and sever- general, the shorter and more polyunsaturated (more cis double bonds)
al purine nucleosides and nucleotides help to maintain a low SAM/SAH the side chain, the more fluid the membrane. Reciprocally, the longer
ratio by inhibiting SAH hydrolase (SAHH), a key enzyme known to be the carbon side chain, and the more saturated, the stiffer the mem-
the target of several synthetic antiviral drugs (De Clercq, 2009). branes become. In the plasma, phosphoethanolamine-containing satu-
rated very long chain fatty acids (PE-VLCFAs) are more abundant
(Pastural et al., 2009). Under conditions of cell danger, both Jumonji
4.8. Ornithine demethylases (Liu et al., 2012) and heme oxygenase I (Nie et al.,
2013) upregulate lipoxygenase expression. The double bonds of fatty
Ornithine is a non-proteogenic amino acid synthesized from argi- acids in the membrane are targets for peroxidation by lipoxygenases.
nine by arginase I in the liver, and arginase II in many other tissues. Under conditions of the CDR, the cell membrane is stiffened by progres-
When the CDR is activated, ornithine is decarboxylated by the B6- sive replacement of shorter polyunsaturated lipids with longer, more
dependent enzyme ornithine decarboxylase (ODC) to putrescine, the saturated lipids. The activation of phospholipase D2 leads to coupling
polyamine used for all higher molecular weight polyamines like of G-protein activation (Mahankali et al., 2011) and release of the potent
spermidine and spermine. Sustained activation of ODC contributes to signaling lipids as phosphatidic acid (Peng and Frohman, 2012). Since a
increased inflammation and the development of autoantibodies in ani- large number of purinergic and other innate immune signaling recep-
mal models of lupus erythematosis (Hsu et al., 1994). tors are G-protein coupled receptors, the early translocation of PLD2
to the membrane has the effect of priming purinergic signaling in the
early steps of the CDR.
4.9. Histidine
4.13. Tryptophan
Acute activation of the CDR stimulates the B6-dependent enzyme
histidine decarboxylase to yield histamine. Histamine is a potent vaso-
The many metabolic fates of tryptophan make it an important mol-
dilator that facilitates the delivery of increased oxygen and immune ef-
ecule in both the early and late stages of the CDR. Tryptophan can be
fector cells to sites of inflammation. Histamine is also critical for mast
metabolized either to serotonin and melatonin via the hydroxylation
cell and eosinophil function in allergy and the anti-parasite limb of in-
(tryptophan hydroxylase) pathway, or to kynurenic acid, quinolinic
nate immunity (Fulkerson and Rothenberg, 2013).
acid, niacin, and the pyridine nucleotides (NAD+, NADP+) via the
dioxygenase (indoleamine 2,3-dioxygenase, IDO) pathway. About
4.10. Arginine 90% of the total body stores of serotonin are synthesized in gut
enterochromaffin cells, and transported in platelets in the form of
Arginine has several fates in metabolism. It is a substrate for the dense, δ-granules, which also contain ADP, ATP, histamine and calcium.
tetrahydrobiopterin-dependent nitric oxide synthase. The resulting Gut microbial metabolism of tryptophan results in the synthesis of a
nitric oxide (NO) gas is a potent and reversible inhibitor of mitochondri- large family of indoles, several of which can also be metabolized to
al cytochrome c oxidase, also known as complex IV (Forstermann kynurenine. Kynurenic acid acts as an endogenous ligand for the aryl
and Sessa, 2012). Arginine can also be decarboxylated to synthesize hydrocarbon receptor and synergistic inducer of IL6 (DiNatale et al.,
agmatine, a natural anti-depressant neurotransmitter (Bernstein et al., 2010), stimulates the innate immune functions like the anti-fungal ac-
2012). Under conditions of the CDR, agmatine is hydrolyzed to produce tivity of neutrophils, and stimulates TH2 cells, while attenuating adap-
urea and the antiviral polyamine, putrescine (Bernstein et al., 2012). tive immunity by the stimulation of TH1-inhibitory, regulatory T cells
(Treg) (Mandi and Vecsei, 2012).

4.11. Heme 4.14. Lysine

Heme is abundant in erythrocyte hemoglobin, but is also present as The antiviral CDR is strongly regulated by the post-translational
an important prosthetic group in the mitochondrial cytochromes of re- state of lysines on histones and immune effector proteins like the
spiratory chain complexes II, III, and IV (Kim et al., 2012). In a sequence double strand RNA binding protein known as RIG1 (retinoic acid induc-
of events that activates the CDR, red cell and mitochondrial heme cen- ible gene 1), and the mitochondrial antiviral sensor (MAVS) (Jiang et al.,
ters are released from damaged cells. In the extracellular space, heme 2012). Lysine ubiquitination facilitates oligomerization of RIG1, which is
is metabolized by heme oxygenase I (HO-1) to produce carbon monox- required for efficient binding to MAVS and interferon induction. SAM-
ide (CO), releasing iron and biliverdin. Like NO, CO is a potent inhibitor mediated lysine methylation stabilizes proteins, inhibits ubiquitination,
of mitochondrial complex IV. In non-erythroid cells, heme is a feedback and works to oppose increased proteasome-mediated protein turnover
inhibitor of porphyrin biosynthesis (Ajioka et al., 2006). that is part of the CDR. Dietary lysine is an antagonist of the gut

Fig. 2. Metabolic features of the cell danger response. A. Twelve branch-point metabolites from mitochondria to phospholipids. Each of the metabolites and effectors indicated can be me-
tabolized in two or more alternative pathways. The pathways indicated in the upward direction in the figure are characteristic of healthy development. They are also active during con-
ditions of caloric restriction, such as those that occurred historically during the winter, during which the maintenance and preservation of limiting resources and energy is essential. The
metabolic pathways indicated in the bottom half of the Figure are active during periods of unrestricted nutrient and resource availability, as is characteristic of the abundance of summer.
When cell division can occur, healthy growth without inflammation results. However, when cell division cannot occur readily, as is the case in many differentiated tissues like the brain,
and physical exercise is limited, innate immune disease and chronic inflammation result. B. Nine branch-point metabolites and effectors from tryptophan to the gut microbiome. The re-
actions illustrated in the bottom half of the Figure are characteristic of the CDR. The list of CDR metabolites and their metabolic fates illustrated in panels A and B is not intended to be
complete. Other metabolites, effectors, and metabolic fates also exist and are coordinately regulated with those indicated, and tailored by metabolic memory to help defend the cell during
danger. When the CDR persists pathologically, chronic disease results.
14 R.K. Naviaux / Mitochondrion 16 (2014) 7–17

serotonin receptor 4 (5HTR4), is anxiolytic (Smriga and Torii, 2003), Gudz, 2011), and targets mitochondria under conditions that lead to
and opposes the CDR. cell death (Sentelle et al., 2012). The cell death or cell survival result of
the CDR depends in part on the balance between S1P and ceramide.
4.15. Cholesterol
4.20. Metals
Unesterified cholesterol increases the shear-stress resistance and ac-
tivation of neutrophils (Zhang et al., 2011). Low cholesterol inhibits cal- Normal metabolism depends critically on the presence of a large
cium activation and oxidative burst in neutrophils (Kannan et al., 2007). number of metals like Mg2+, Ca2+, Fe2+, Cu+, Zn2+, Mn2+, Mo4+,
High cholesterol also makes neuronal cells more resistant to the cyto- Se2+, and Co2+ that interact with nucleotides and other metabolites,
toxic effects of amyloid beta peptides (AβP) (Arispe and Doh, 2002). and with proteins to stabilize structure and create organometallic reac-
The plasma membrane of many eukaryotic cells consists of nearly tion centers. Many other metals like Pb, Hg, As, V, Ni, Al, Cd, Ce, and Cr
50 mol% unesterified cholesterol, which acts as an intramembrane are toxic. Under reducing redox conditions of cell health, these toxic
space filler, with a small polar head group (a single hydroxyl), to help metals are not accumulated because excretion normally exceeds expo-
solubilize phospholipids. Cholesterol accumulates with GM1 ganglio- sure. When the CDR is activated, the oxidizing intracellular conditions
side in microdomains called caveolae that continuously sample the favor sequestration, toxic amounts of trace and heavy metals can be
pericellular environment. When the cell is activated, GM1 and choles- accumulated, and are not easily mobilized. Many toxic metals act not
terol concentrate to form lipid rafts, which cause many proteins to only as electrophiles because of their positive charge, but are also
patch and concentrate into the rafts for more efficient anti-microbial de- sulfurophiles—they readily form sulfides with free thiols of cysteine,
fense. CDR proteins like the formyl peptide receptor and NADPH oxidase and glutathione. This makes free thiols unavailable for normal metabolic
(NOX) are assembled in lipid rafts for efficient ROS production (Jin and reactions and can create a condition known as pseudohypoxia in which
Zhou, 2009). intrapeptide cysteine residues of redox-sensing proteins remain
uncrosslinked, disulfide bonds cannot form normally, and the three di-
4.16. Vitamin B6 mensional structure of the reduced form of the protein is favored
under normal oxygen concentrations that would otherwise stabilize di-
Low plasma levels of the active metabolite of vitamin B6, pyridoxal sulfide bonding. In addition to these effects, the more specific neurotox-
5′-phosphate (PLP) are a common feature of inflammation and the ic effects of metals like lead and mercury are well known (Ibrahim et al.,
CDR (Paul et al., 2013). PLP is a cofactor in 4 reactions in the dioxygenase 2006). When functional vitamin D is decreased by a chronically active
(IDO) pathway of tryptophan metabolism, after the formation of CDR, subclinical renal wasting of magnesium can occur (Sutton and
kynurenine, leading to the synthesis of quinolinic acid and NAD+ and Domrongkitchaiporn, 1993).
NADP+. PLP is also required by the enzyme S1P lyase for inactivating
the lymphocyte chemoattractant sphingosine-1-phosphate (S1P). 4.21. Gut microbiome
Low systemic levels of PLP have the effect of increasing the kynurenine/
tryptophan ratio, and increase S1P in inflamed tissues, thereby sustaining Healthy metabolism acts as a survival engine that computes the op-
an active CDR. timum chemical solution for fitness based on the developmental histo-
ry, current environmental conditions, and the genetic resources
4.17. Arachidonate available to the individual. When we sample blood or urine, we are
actually sampling the collective metabolism of the host-microbiome
Cells that are especially rich in mitochondria, like brain, nerve, and system. This collective metabolism also controls the epigenetic modifi-
epithelial cells, are also rich in plasmalogen lipids, which contain arachi- cation of DNA in somatic cells that creates long-term changes in gene
donic acid in the sn-2 position. This is the preferred substrate for phos- expression (Naviaux, 2008). The human metabotype consists of a dy-
pholipase A2 (PLA2) isoforms for the release of arachidonate for namically regulated core vocabulary of about 400–1200 chemical
prostaglandin, leukotriene, and other inflammatory lipid synthesis words that cells use to communicate. These are small molecule metab-
(Ong et al., 2010) during an active CDR. olites with a mass less than 2000 Da in size. The stoichiometric propor-
tions of these metabolites are a reflection of our state of health at the
4.18. Sphingosine time of sampling. The adult human body consists of about 1014 human
cells and 1015 bacterial cells that act as a living shield to help protect
Several intracellular pathogens have evolved mechanisms to either us from opportunistic pathogens and keep us healthy. About 99% of
inhibit the synthesis and translocation of sphingosine 1-phosphate our microbiome is in our gut. The biomass of our microbiome is about
(S1P) (Thompson et al., 2005), or stimulate its degradation in mito- 1.5 kg, or about 2% of our body weight. Collectively, the bacteria, ar-
chondria (Degtyar et al., 2009). S1P is a phosphorylated sphingolipid chaea, rare fungi, protists, and invertebrate metazoans that constitute
that contains a single fatty acid linked to a phosphoserine head group. the 3000 to 30,000 species in our gut microbiome contain a genetic
Intracellular S1P traffics to phagosomes where it facilitates calcium- complexity of about 4.5 × 1011 Gb—about 150 fold more genetic infor-
dependent acidification during autophagy and the elimination of intra- mation than in the human haploid genome. This is evidence that the
cellular parasites and modulates histone acetylation in the nucleus metabolic diversity in the gut microbiome far exceeds that of the
(Lucki and Sewer, 2012). Extracellular S1P binds to 5 G-protein linked human host.
receptors, acts to inhibit apoptosis, prevents lymphocyte egress from The composition and function of the microbiome are best considered
sites of production as well as sites of inflammation (Takabe et al., as an ecosystem that is continuously shaped by the developmental his-
2008), and is essential for normal development of hearing and vestibu- tory, diet, health, and activity of the host. As with any ecosystem, the
lar function (MacLennan et al., 2006). S1P opposes the immunomodula- health and species composition of the microbiome are determined by
tory effects of kynurenine by inhibiting Tregs, stimulating TH1, and a discrete set of forcing variables that include the physical habitat, re-
activating mTOR (Liu et al., 2010). sources, complementary biodiversity, disruptive biodiversity (invasive
species), and the recycling and removal of metabolic end products.
4.19. Ceramide When the host is sick, the microbiome is also sick. The chronic activation
of the CDR alters both the physical habitat of the distal bowel and the
Ceramide is the precursor to GM1 ganglioside, sphingosine, and S1P. availability of resources in the form of dietary nutrients. For example,
Ceramide both requires mitochondria for synthesis (Novgorodov and in children with autism spectrum disorders (ASD), the expression of
 R.K. Naviaux / Mitochondrion 16 (2014) 7–17 15

intestinal disaccharidases is decreased so that the microbiota of the dis- Table 1

tal bowel receives a larger number of simple disaccharides like sucrose, Disorders corrected or improved by antipurinergic therapy.

lactose, and maltose (Williams et al., 2011). In addition, the increase in Disease Species Antipurinergic Reference
oxidizing conditions associated with the CDR in cells lining the intestine drug
leads to changes in the uptake, intracellular processing, and folding of Autism Mice Suramin Naviaux et al. (2013)
the proline and glutamine-rich, processed gliadin 33-mer peptide Spinal cord injury Rats Brilliant Blue G Peng et al. (2009)
(Oguma et al., 2007), and to an increase in gluten sensitivity (Jacobs, Traumatic brain injury Rats and Mice MRS2179 Choo et al. (2013)
Ischemic brain injury Rats Suramin Kharlamov et al. (2002)
2007). These and other factors combine to alter the permeability and
Glutamate excitotoxicity Rats Suramin Bezvenyuk et al. (2000)
species composition in the gut. Among children with ASD, this Epilepsy Mice A438079 Engel et al. (2012)
commonly leads to dysbiosis and alternating bouts of constipation and Rheumatoid arthritis Rats Suramin Sahu et al. (2012))
diarrhea. It also leads to changes in behavior that are a result of commu- Chronic pain Rats P2X3-15h Cantin et al. (2012)
nication abnormalities between the enteric nervous system (ENS) that Multiple sclerosis Mice Suramin Novales-Li (1996)
Lupus erythematosis Mice Suramin Ballok and Sakic (2008)
monitors the health and function of the microbiome, and the central
Restenosis after Rabbits Suramin Gray et al. (1999)
nervous system (CNS). Restoring a sick microbiome is not as simple as angioplasty
adding back missing or underrepresented species. Both the physical Duchenne Mice Suramin de Oliveira Moreira et al.
habitat of the gut and the nutrient resources delivered must be durably cardiomyopathy (2013)
Heart failure Rats Apyrase Marina et al. (2013)
changed in order to produce a durable change in the complex microbial
Alcoholic liver Rats Suramin He et al. (2013))
ecosystem. disease/cirrhosis
Asthma Guinea Pigs Suramin Oguma et al. (2007)
5. Resolution of the CDR Emphysema Mice Suramin Cicko et al. (2010)
Diabetic kidney disease Rats Suramin Korrapati et al. (2012)

Once the danger has been eliminated or neutralized, two things hap-
pen naturally. First, a choreographed sequence of anti-inflammatory
and regenerative pathways is activated that helps replace lost cells
exposure determine the risk of developing a particular disease. In
and restore normal organ function (Heber-Katz and Stocum, 2013).
many cases, it appears that mixtures of cell danger exposures are re-
Next, a metabolic memory of the exposure that led to the CDR is stored
quired. When the abnormalities appear later in childhood or young
in a way similar to the way the brain stores memories, in the form of du-
adult life, and have not persisted long enough to produce structural ab-
rable changes in mitochondrial biomass, and cellular protein, lipid and
normalities, there is a chance that many disorders currently thought to
other macromolecule content, cell structure, and gene expression via
be static, irreversible, and poorly responsive to treatment, or even de-
somatic epigenetic modifications (Naviaux, 2008). This metabolic mem-
generative, might actually be dynamic functional states that respond
ory is also called mitocellular hormesis (Naviaux, 2012). Under condi-
well to anti-CDR treatments. Many of the disorders named above have
tions that are determined by a mixture of host genotype, and the
already shown response to APT in animal models (Table 1). An impor-
character, developmental timing, magnitude, and frequency of expo-
tant caveat to APT is that if the physical, chemical, or biological trigger
sure, a dysfunctional form of the CDR can persist that leads to chronic
of the CDR has not been eliminated or neutralized, treatments
disease. Because the CDR is initially adaptive and coordinated by the
designed to inhibit a persistent CDR may have mixed effects. For ex-
close interplay of mitochondria and the cell, but becomes maladaptive
ample, if the CDR is a response to perinatal exposure to PBDE flame
once the environmental danger is gone, this can be referred to as
retardants (Blumberg et al., 2013), but the PBDEs have not been re-
“anachroadaptive mitocellular dysfunction”.
moved from living space of an affected child, then a persistent CDR
can be adaptive and not anachroadaptive. APT under these condi-
6. Disease implications and summary
tions may cause net harm.
Each of the metabolic features of the CDR illustrated in Figs. 1 and
When the CDR fails to resolve, chronic disease results. Beginning in
2AB can be addressed individually with specific treatments, or more
the first trimester, the brainstem is responsible for the chemosensory
globally with a combination of supplements, dietary and activity
integration of whole body metabolism with neurodevelopment. After
changes, or with adaptogen therapies (Panossian and Wikman, 2009).
birth, the trajectory of normal development can be altered if the CDR
However, since the CDR appears to be a functional response that is coor-
and its attendant metabolic changes persist. Some of the diseases that
dinated by purinergic signaling, a new chapter in complex disease ther-
result from a pathological persistence of the CDR include: autism spec-
apeutics can be imagined in which the pharmacology of purinergic
trum disorders (ASD), attention deficit hyperactivity disorder (ADHD),
antagonists is expanded, natural products are sought, and new anti-
food allergies, asthma, atopy, emphysema, Tourette's syndrome, bipolar
inflammatory drugs are developed that selectively target one or more
disorder, schizophrenia, post-traumatic stress disorder (PTSD), trau-
of the 19 known classes of purinergic receptors.
matic brain injury (TBI), chronic traumatic encephalopathy (CTE),
suicidal ideation, ischemic brain injury, spinal cord injury, diabetes, kid-
ney, liver, and heart disease, cancer, Alzheimer and Parkinson disease,
Acknowledgments
and autoimmune disorders like lupus, rheumatoid arthritis, multiple
sclerosis, and primary sclerosing cholangitis. Pathological persistence
RKN thanks Jane Naviaux, Will Alaynick, Jim Adams, Steve Edelson,
of the CDR can occur after the inciting agent has gone. This can be
Kate Crowley, and Vicki Kobliner for helpful comments on the manu-
the result of hormesis and metabolic memory, somatic epigenetic
script. This work was made possible by support from the UCSD Christini
changes (Blumberg et al., 2013), or both. Purinergic signaling ap-
Fund, the Jane Botsford Johnson Foundation, the Wright Foundation,
pears to play an important role in sustaining the multifaceted meta-
the Lennox Foundation, the It Takes Guts Foundation, the UCSD Mi-
bolic features of the CDR. This observation led to the successful
tochondrial Disease Research Foundation, and the Hailey's Wish
correction of all 16 of 16 multi-system, autism-like features in a
Foundation.
classic animal model of ASD using antipurinergic therapy (APT)
(Naviaux et al., 2013).
The chronic CDR disorders listed above produce abnormalities in a Conflict of interest
broad range of target tissues and cell types. The genotype and health
of the host, and the developmental timing and the nature of the None.
16 R.K. Naviaux / Mitochondrion 16 (2014) 7–17

References Eisner, V., Parra, V., Lavandero, S., Hidalgo, C., Jaimovich, E., 2010. Mitochondria fine-tune
the slow Ca(2+) transients induced by electrical stimulation of skeletal myotubes.
Ajioka, R.S., Phillips, J.D., Kushner, J.P., 2006. Biosynthesis of heme in mammals. Biochim. Cell Calcium 48, 358–370.
Biophys. Acta 1763, 723–736. Engel, T., Gomez-Villafuertes, R., Tanaka, K., Mesuret, G., Sanz-Rodriguez, A., Garcia-
Angata, T., Fujinawa, R., Kurimoto, A., Nakajima, K., Kato, M., Takamatsu, S., Korekane, H., Huerta, P., Miras-Portugal, M.T., Henshall, D.C., Diaz-Hernandez, M., 2012. Seizure
Gao, C.X., Ohtsubo, K., Kitazume, S., Taniguchi, N., 2012. Integrated approach toward suppression and neuroprotection by targeting the purinergic P2X7 receptor during
the discovery of glyco-biomarkers of inflammation-related diseases. Ann. N. Y. Acad. status epilepticus in mice. FASEB J. 26, 1616–1628.
Sci. 1253, 159–169. Fontecave, M., Atta, M., Mulliez, E., 2004. S-adenosylmethionine: nothing goes to waste.
Arispe, N., Doh, M., 2002. Plasma membrane cholesterol controls the cytotoxicity of Trends Biochem. Sci. 29, 243–249.
Alzheimer's disease AbetaP (1–40) and (1–42) peptides. FASEB J. 16, 1526–1536. Forstermann, U., Sessa, W.C., 2012. Nitric oxide synthases: regulation and function.
Arnoult, D., Soares, F., Tattoli, I., Girardin, S.E., 2011. Mitochondria in innate immunity. Eur. Hear. J. 33, 829–837.
EMBO Rep. 12, 901–910. Fuchs, E.J., Matzinger, P., 1996. Is cancer dangerous to the immune system? Semin.
Bachrach, U., 2007. Antiviral activity of oxidized polyamines. Amino Acids 33, 267–272. Immunol. 8, 271–280.
Ballok, D.A., Sakic, B., 2008. Purine receptor antagonist modulates serology and affective Fulkerson, P.C., Rothenberg, M.E., 2013. Targeting eosinophils in allergy, inflammation
behaviors in lupus-prone mice: evidence of autoimmune-induced pain? Brain and beyond. Nat. Rev. Drug Discov. 12, 117–129.
Behav. Immun. 22, 1208–1216. Garrod, A.E., 1902. The incidence of alkaptonuria: a study in chemical individuality. Lancet
Bernstein, H.G., Stich, C., Jager, K., Dobrowolny, H., Wick, M., Steiner, J., Veh, R., Bogerts, B., 12, 1616–1620.
Laube, G., 2012. Agmatinase, an inactivator of the putative endogenous antidepres- Gray, T.J., Strauss, B.H., Hinek, A., 1999. Inhibitory mechanisms by which suramin may at-
sant agmatine, is strongly upregulated in hippocampal interneurons of subjects tenuate neointimal formation after balloon angioplasty. J. Cardiovasc. Pharmacol. 33,
with mood disorders. Neuropharmacology 62, 237–246. 960–971.
Bezvenyuk, Z., Suuronen, T., Salminen, A., Solovyan, V., 2000. Protective effect of suramin Gunderson, L.H., 2000. Ecological resilience — in theory and application. Annu. Rev. Ecol.
against cell death in rat cerebellar granular neurons and mouse neuroblastoma cells. Syst. 31, 425–439.
Neurosci. Lett. 292, 111–114. Halassa, M.M., 2011. Thalamocortical dynamics of sleep: roles of purinergic neuro-
Blumberg, S.J., Bramlett, M.D., Kogan, M.D., Schieve, L.A., Jones, J.R., Lu, M.C., 2013. Changes modulation. Semin. Cell Dev. Biol. 22, 245–251.
in prevalence of parent-reported autism spectrum disorder in school-aged U.S. Haynes, C.M., Fiorese, C.J., Lin, Y.F., 2013. Evaluating and responding to mitochondrial dys-
children: 2007 to 2011–2012. Natl. Health Stat. Report 65, 1–12. function: the mitochondrial unfolded-protein response and beyond. Trends Cell Biol.
Bours, M.J., Dagnelie, P.C., Giuliani, A.L., Wesselius, A., Di Virgilio, F., 2011. P2 receptors 23, 311–318.
and extracellular ATP: a novel homeostatic pathway in inflammation. Front Biosci. He, S., Rehman, H., Shi, Y., Krishnasamy, Y., Lemasters, J.J., Schnellmann, R.G., Zhong, Z.,
(Schol Ed) 3, 1443–1456. 2013. Suramin decreases injury and improves regeneration of ethanol-induced
Bridges, R.J., Natale, N.R., Patel, S.A., 2012. System xc(−) cystine/glutamate antiporter: steatotic partial liver grafts. J. Pharmacol. Exp. Ther. 344, 417–425.
an update on molecular pharmacology and roles within the CNS. Br. J. Pharmacol. Heber-Katz, E., Stocum, D.L., 2013. New Perspectives in Regeneration. Springer,
165, 20–34. New York, NY.
Burnstock, G., 2012. Targeting the visceral purinergic system for pain control. Curr. Opin. Hecker, L., Vittal, R., Jones, T., Jagirdar, R., Luckhardt, T.R., Horowitz, J.C., Pennathur, S.,
Pharmacol. 12, 80–86. Martinez, F.J., Thannickal, V.J., 2009. NADPH oxidase-4 mediates myofibroblast activa-
Burnstock, G., Verkhratsky, A., 2009. Evolutionary origins of the purinergic signalling sys- tion and fibrogenic responses to lung injury. Nat. Med. 15, 1077–1081.
tem. Acta Physiol. (Oxf) 195, 415–447. Hsu, H.C., Seibold, J.R., Thomas, T.J., 1994. Regulation of ornithine decarboxylase in the
Burnstock, G., Dumsday, B., Smythe, A., 1972. Atropine resistant excitation of the urinary kidney of autoimmune mice with the lpr gene. Autoimmunity 19, 253–264.
bladder: the possibility of transmission via nerves releasing a purine nucleotide. Hultqvist, M., Olsson, L.M., Gelderman, K.A., Holmdahl, R., 2009. The protective role of ROS
Br. J. Pharmacol. 44, 451–461. in autoimmune disease. Trends Immunol. 30, 201–208.
Burnstock, G., Fredholm, B.B., North, R.A., Verkhratsky, A., 2010. The birth and postnatal Ibrahim, D., Froberg, B., Wolf, A., Rusyniak, D.E., 2006. Heavy metal poisoning: clinical pre-
development of purinergic signalling. Acta Physiol (Oxf) 199, 93–147. sentations and pathophysiology. Clin. Lab. Med. 26, 67–97 (viii).
Burnstock, G., Krugel, U., Abbracchio, M.P., Illes, P., 2011. Purinergic signalling: from nor- Jacobs, S.A., 2007. Celiac sprue is primarily a disease of blocked cellular recognition.
mal behaviour to pathological brain function. Prog. Neurobiol. 95, 229–274. Med. Hypotheses 68, 308–313.
Caccamo, D., Curro, M., Ferlazzo, N., Condello, S., Ientile, R., 2012. Monitoring of Jiang, X., Kinch, L.N., Brautigam, C.A., Chen, X., Du, F., Grishin, N.V., Chen, Z.J., 2012.
transglutaminase 2 under different oxidative stress conditions. Amino Acids 42, Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates
1037–1043. antiviral innate immune response. Immunity 36, 959–973.
Cantin, L.D., Bayrakdarian, M., Buon, C., Grazzini, E., Hu, Y.J., Labrecque, J., Leung, C., Luo, X., Jin, S., Zhou, F., 2009. Lipid raft redox signaling platforms in vascular dysfunction: features
Martino, G., Pare, M., Payza, K., Popovic, N., Projean, D., Santhakumar, V., Walpole, C., and mechanisms. Curr. Atheroscler. Rep. 11, 220–226.
Yu, X.H., Tomaszewski, M.J., 2012. Discovery of P2X3 selective antagonists for the Junger, W.G., 2011. Immune cell regulation by autocrine purinergic signalling. Nat. Rev.
treatment of chronic pain. Bioorg. Med. Chem. Lett. 22, 2565–2571. Immunol. 11, 201–212.
Cervelli, M., Amendola, R., Polticelli, F., Mariottini, P., 2012. Spermine oxidase: ten years Kannan, K.B., Barlos, D., Hauser, C.J., 2007. Free cholesterol alters lipid raft structure and
after. Amino acids 42, 441–450. function regulating neutrophil Ca2+ entry and respiratory burst: correlations with
Choo, A.M., Miller, W.J., Chen, Y.C., Nibley, P., Patel, T.P., Goletiani, C., Morrison III, B., calcium channel raft trafficking. J. Immunol. 178, 5253–5261.
Kutzing, M.K., Firestein, B.L., Sul, J.Y., Haydon, P.G., Meaney, D.F., 2013. Antagonism Kawamura, M., Matsui, T., Niitsu, A., Kondo, T., Ohno, Y., Nakamichi, N., 1991. Extracellular
of purinergic signalling improves recovery from traumatic brain injury. Brain 136, ATP stimulates steroidogenesis in bovine adrenocortical fasciculata cells via P2
65–80. purinoceptors. Jpn. J. Pharmacol. 56, 543–545.
Cicko, S., Lucattelli, M., Muller, T., Lommatzsch, M., De Cunto, G., Cardini, S., Sundas, W., Kharlamov, A., Jones, S.C., Kim, D.K., 2002. Suramin reduces infarct volume in a model of
Grimm, M., Zeiser, R., Durk, T., Zissel, G., Boeynaems, J.M., Sorichter, S., Ferrari, D., focal brain ischemia in rats. Exp. Brain Res. 147, 353–359.
Di Virgilio, F., Virchow, J.C., Lungarella, G., Idzko, M., 2010. Purinergic receptor inhibi- Kim, H.P., Morse, D., Choi, A.M., 2006. Heat-shock proteins: new keys to the development
tion prevents the development of smoke-induced lung injury and emphysema. of cytoprotective therapies. Expert Opin. Ther. Targets 10, 759–769.
J. Immunol. 185, 688–697. Kim, H.J., Khalimonchuk, O., Smith, P.M., Winge, D.R., 2012. Structure, function, and as-
Corcoran, J.A., Saffran, H.A., Duguay, B.A., Smiley, J.R., 2009. Herpes simplex virus UL12.5 sembly of heme centers in mitochondrial respiratory complexes. Biochim. Biophys.
targets mitochondria through a mitochondrial localization sequence proximal to Acta 1823, 1604–1616.
the N terminus. J. Virol. 83, 2601–2610. Kivity, S., Agmon-Levin, N., Zisappl, M., Shapira, Y., Nagy, E.V., Danko, K., Szekanecz, Z.,
Darwin, C.R., 1839. Journal and remarks, 1832–1836. In: Nicholas, F.W., Nicholas, J.M. Langevitz, P., Shoenfeld, Y., 2011. Vitamin D and autoimmune thyroid diseases. Cell.
(Eds.), Charles Darwin in Australia. Cambridge University Press, Cambridge, Mol. Immunol. 8, 243–247.
pp. 30–31. Knight, J.C., 2013. Genomic modulators of the immune response. Trends Genet. 29, 74–83.
De Clercq, E., 2009. Another ten stories in antiviral drug discovery (part C): “old” and Kobayashi, S., Kuwata, K., Sugimoto, T., Igarashi, K., Osaki, M., Okada, F., Fujii, J., Bannai, S.,
“new” antivirals, strategies, and perspectives. Med. Res. Rev. 29, 611–645. Sato, H., 2012. Enhanced expression of cystine/glutamate transporter in the lung caused
de Oliveira Moreira, D., Pereira, J.A., Taniguti, A.P., Matsumura, C.Y., Ramos, L.A., Areas, by the oxidative-stress-inducing agent paraquat. Free Radic. Biol. Med. 53, 2197–2203.
M.A., Neto, H.S., Marques, M.J., 2013. Suramin attenuates dystrophin-deficient cardio- Korrapati, M.C., Shaner, B.E., Neely, B.A., Alge, J.L., Arthur, J.M., Schnellmann, R.G., 2012.
myopathy in the mdx mouse model of Duchenne muscular dystrophy. Muscle Nerve. Diabetes-induced renal injury in rats is attenuated by suramin. J. Pharmacol. Exp.
Degtyar, E., Zusman, T., Ehrlich, M., Segal, G., 2009. A Legionella effector acquired from Ther. 343, 34–43.
protozoa is involved in sphingolipids metabolism and is targeted to the host cell mi- Kruidenier, L., Chung, C.W., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra,
tochondria. Cell. Microbiol. 11, 1219–1235. C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., Jones, E., Katso, R., Leveridge, M.,
DiNatale, B.C., Murray, I.A., Schroeder, J.C., Flaveny, C.A., Lahoti, T.S., Laurenzana, E.M., Mander, P.K., Mosley, J., Ramirez-Molina, C., Rowland, P., Schofield, C.J., Sheppard, R.J.,
Omiecinski, C.J., Perdew, G.H., 2010. Kynurenic acid is a potent endogenous aryl hy- Smith, J.E., Swales, C., Tanner, R., Thomas, P., Tumber, A., Drewes, G., Oppermann, U.,
drocarbon receptor ligand that synergistically induces interleukin-6 in the presence Patel, D.J., Lee, K., Wilson, D.M., 2012. A selective jumonji H3K27 demethylase inhib-
of inflammatory signaling. Toxicol. Sci. 115, 89–97. itor modulates the proinflammatory macrophage response. Nature 488, 404–408.
Dreifus, C., 1998. A Conversation With Polly Matzinger; Blazing an Unconventional Trail Kuijpers, T., Lutter, R., 2012. Inflammation and repeated infections in CGD: two sides of a
to a New Theory of Immunity. The New York Times, Science. June 16, 1998. coin. Cell Mol. Life Sci. 69, 7–15.
Edmonds, J.L., Kirse, D.J., Kearns, D., Deutsch, R., Spruijt, L., Naviaux, R.K., 2002. The Landrigan, P., Lambertini, L., Birnbaum, L., 2012. A research strategy to discover the envi-
otolaryngological manifestations of mitochondrial disease and the risk of neuro- ronmental causes of autism and neurodevelopmental disabilities. Environ. Heal.
degeneration with infection. Arch. Otolaryngol. Head Neck Surg. 128, 355–362. Perspect. 120, a258–a260.
Ehlert, U., 2013. Enduring psychobiological effects of childhood adversity. Lee, A.H., Glimcher, L.H., 2009. Intersection of the unfolded protein response and hepatic
Psychoneuroendocrinology (Electronic publication ahead of print). lipid metabolism. Cell Mol. Life Sci. 66, 2835–2850.
 R.K. Naviaux / Mitochondrion 16 (2014) 7–17 17

Lesch, M., Nyhan, W.L., 1964. A familial disorder of uric acid metabolism and central ner- autism: mitochondrial dysfunction as a putative causative mechanism. Prostaglan-
vous system function. Am. J. Med. 36, 561–570. dins Leukot. Essent. Fat. Acids 81, 253–264.
Lewerenz, J., Hewett, S.J., Huang, Y., Lambros, M., Gout, P.W., Kalivas, P.W., Massie, A., Paul, L., Ueland, P.M., Selhub, J., 2013. Mechanistic perspective on the relationship be-
Smolders, I., Methner, A., Pergande, M., Smith, S.B., Ganapathy, V., Maher, P., 2013. tween pyridoxal 5′-phosphate and inflammation. Nutr. Rev. 71, 239–244.
The cystine/glutamate antiporter system x(c)(−) in health and disease: from Peng, X., Frohman, M.A., 2012. Mammalian phospholipase D physiological and patholog-
molecular mechanisms to novel therapeutic opportunities. Antioxid. Redox Signal. ical roles. Acta Physiol (Oxf) 204, 219–226.
18, 522–555. Peng, W., Cotrina, M.L., Han, X., Yu, H., Bekar, L., Blum, L., Takano, T., Tian, G.F., Goldman,
Liu, G., Sun, Y., Li, Z., Song, T., Wang, H., Zhang, Y., Ge, Z., 2008. Apoptosis induced by S.A., Nedergaard, M., 2009. Systemic administration of an antagonist of the ATP-
endoplasmic reticulum stress involved in diabetic kidney disease. Biochem. Biophys. sensitive receptor P2X7 improves recovery after spinal cord injury. Proc. Natl. Acad.
Res. Commun. 370, 651–656. Sci. U. S. A. 106, 12489–12493.
Liu, G., Yang, K., Burns, S., Shrestha, S., Chi, H., 2010. The S1P(1)-mTOR axis directs Pimentel, V.C., Zanini, D., Cardoso, A.M., Schmatz, R., Bagatini, M.D., Gutierres, J.M.,
the reciprocal differentiation of T(H)1 and T(reg) cells. Nat. Immunol. 11, Carvalho, F., Gomes, J.L., Rubin, M., Morsch, V.M., Moretto, M.B., Colino-Oliveira, M.,
1047–1056. Sebastiao, A.M., Schetinger, M.R., 2013. Hypoxia-ischemia alters nucleotide and nu-
Liu, C., Xu, D., Han, H., Fan, Y., Schain, F., Xu, Z., Claesson, H.E., Bjorkholm, M., Sjoberg, J., cleoside catabolism and Na+, K+-ATPase activity in the cerebral cortex of newborn
2012. Transcriptional regulation of 15-lipoxygenase expression by histone h3 lysine rats. Neurochem. Res. 38, 886–894.
4 methylation/demethylation. PLoS One 7, e52703. Rabiet, M.J., Huet, E., Boulay, F., 2005. Human mitochondria-derived N-formylated peptides
Lluis, J.M., Buricchi, F., Chiarugi, P., Morales, A., Fernandez-Checa, J.C., 2007. Dual role of are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-
mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear derived peptides preferentially activate FPR. Eur. J. Immunol. 35, 2486–2495.
factor-{kappa}B via c-SRC and oxidant-dependent cell death. Cancer Res. 67, Riegl, B., Bruckner, A., Coles, S.L., Renaud, P., Dodge, R.E., 2009. Coral reefs: threats and
7368–7377. conservation in an era of global change. Ann. N. Y. Acad. Sci. 1162, 136–186.
Lucki, N.C., Sewer, M.B., 2012. Nuclear sphingolipid metabolism. Annu. Rev. Physiol. 74, Riteau, N., Baron, L., Villeret, B., Guillou, N., Savigny, F., Ryffel, B., Rassendren, F., Le Bert, M.,
131–151. Gombault, A., Couillin, I., 2012. ATP release and purinergic signaling: a common path-
Lushchak, V.I., 2010. Adaptive response to oxidative stress: bacteria, fungi, plants and way for particle-mediated inflammasome activation. Cell Death Dis. 3, e403.
animals. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 153, 175–190. Romero, P., Wagg, J., Green, M.L., Kaiser, D., Krummenacker, M., Karp, P.D., 2005. Compu-
MacLennan, A.J., Benner, S.J., Andringa, A., Chaves, A.H., Rosing, J.L., Vesey, R., tational prediction of human metabolic pathways from the complete human genome.
Karpman, A.M., Cronier, S.A., Lee, N., Erway, L.C., Miller, M.L., 2006. The S1P2 Genome Biol. 6, R2.
sphingosine 1-phosphate receptor is essential for auditory and vestibular func- Sahu, D., Saroha, A., Roy, S., Das, S., Srivastava, P.S., Das, H.R., 2012. Suramin ameliorates
tion. Hear. Res. 220, 38–48. collagen induced arthritis. Int. Immunopharmacol. 12, 288–293.
Mahankali, M., Peng, H.J., Henkels, K.M., Dinauer, M.C., Gomez-Cambronero, J., 2011. Salminen, A., Kaarniranta, K., 2012. AMP-activated protein kinase (AMPK) controls the
Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the aging process via an integrated signaling network. Ageing Res. Rev. 11, 230–241.
GTPase Rac2. Proc. Natl. Acad. Sci. U. S. A. 108, 19617–19622. Scott, I., 2010. The role of mitochondria in the mammalian antiviral defense system. Mi-
Mandi, Y., Vecsei, L., 2012. The kynurenine system and immunoregulation. J. Neural tochondrion 10, 316–320.
Transm. 119, 197–209. Sentelle, R.D., Senkal, C.E., Jiang, W., Ponnusamy, S., Gencer, S., Selvam, S.P., Ramshesh,
Marina, N., Tang, F., Figueiredo, M., Mastitskaya, S., Kasimov, V., Mohamed-Ali, V., Roloff, V.K., Peterson, Y.K., Lemasters, J.J., Szulc, Z.M., Bielawski, J., Ogretmen, B., 2012. Cer-
E., Teschemacher, A.G., Gourine, A.V., Kasparov, S., 2013. Purinergic signalling in the amide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat.
rostral ventro-lateral medulla controls sympathetic drive and contributes to the pro- Chem. Biol. 8, 831–838.
gression of heart failure following myocardial infarction in rats. Basic Res. Cardiol. Seong, S.Y., Matzinger, P., 2004. Hydrophobicity: an ancient damage-associated molecular
108, 317. pattern that initiates innate immune responses. Nat. Rev. Immunol. 4, 469–478.
Matzinger, P., 1994. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, Seth, R.B., Sun, L., Ea, C.K., Chen, Z.J., 2005. Identification and characterization of MAVS, a
991–1045. mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122,
Matzinger, P., Kamala, T., 2011. Tissue-based class control: the other side of tolerance. Nat. 669–682.
Rev. Immunol. 11, 221–230. Shanmugasundaram, R., Selvaraj, R.K., 2012. Vitamin D-1alpha-hydroxylase and vitamin
McLain, A.L., Cormier, P.J., Kinter, M., Szweda, L.I., 2013. Glutathionylation of alpha- D-24-hydroxylase mRNA studies in chickens. Poult. Sci. 91, 1819–1824.
ketoglutarate dehydrogenase: the chemical nature and relative susceptibility of the Silva, J.M., Wong, A., Carelli, V., Cortopassi, G.A., 2009. Inhibition of mitochondrial function
cofactor lipoic acid to modification. Free Radic. Biol. Med. 61C, 161–169. induces an integrated stress response in oligodendroglia. Neurobiol. Dis. 34, 357–365.
Micheli, V., Camici, M., Tozzi, M.G., Ipata, P.L., Sestini, S., Bertelli, M., Pompucci, G., 2011. Smriga, M., Torii, K., 2003. L-Lysine acts like a partial serotonin receptor 4 antagonist and
Neurological disorders of purine and pyrimidine metabolism. Curr. Top Med. Chem. inhibits serotonin-mediated intestinal pathologies and anxiety in rats. Proc. Natl.
11, 923–947. Acad. Sci. U. S. A. 100, 15370–15375.
Nathanson, N., Kew, O.M., 2010. From emergence to eradication: the epidemiology of po- Stipanuk, M.H., Ueki, I., 2011. Dealing with methionine/homocysteine sulfur: cysteine
liomyelitis deconstructed. Am. J. Epidemiol. 172, 1213–1229. metabolism to taurine and inorganic sulfur. J. Inherit. Metab. Dis. 34, 17–32.
Naviaux, R.K., 2008. Mitochondrial control of epigenetics. Cancer Biol. Ther. 7, 1191–1193. Sutton, R.A., Domrongkitchaiporn, S., 1993. Abnormal renal magnesium handling. Miner.
Naviaux, R.K., 2012. Oxidative shielding or oxidative stress? J. Pharmacol. Exp. Ther. 342, Electrolyte Metab. 19, 232–240.
608–618. Takabe, K., Paugh, S.W., Milstien, S., Spiegel, S., 2008. “Inside-out” signaling of
Naviaux, R.K., Zolkipli, Z., Wang, L., Nakayama, T., Naviaux, J.C., Le, T.P., Schuchbauer, M.A., sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev. 60, 181–195.
Rogac, M., Tang, Q., Dugan, L.L., Powell, S.B., 2013. Antipurinergic therapy corrects the Thompson, C.R., Iyer, S.S., Melrose, N., VanOosten, R., Johnson, K., Pitson, S.M., Obeid, L.M.,
autism-like features in the poly(IC) mouse model. PLoS One 8, e57380. Kusner, D.J., 2005. Sphingosine kinase 1 (SK1) is recruited to nascent phagosomes in
Nie, X., Hui, Y., Shi, S., Ma, J., Wang, S., Qiu, Z., Song, S., Pan, Z., Li, Q., Gao, X., Zhu, D., 2013. human macrophages: inhibition of SK1 translocation by Mycobacterium tuberculosis.
Heme oxygenase-1 induces 15-lipoxygenase expression during hypoxia-induced J. Immunol. 174, 3551–3561.
pulmonary hypertension. Int. J. Biochem. Cell Biol. 45, 964–972. West, A.P., Shadel, G.S., Ghosh, S., 2011. Mitochondria in innate immune responses. Nat.
Nielsen, M.J., Rasmussen, M.R., Andersen, C.B., Nexo, E., Moestrup, S.K., 2012. Vitamin B12 Rev. Immunol. 11, 389–402.
transport from food to the body's cells — a sophisticated, multistep pathway. Nat. Williams, B.L., Hornig, M., Buie, T., Bauman, M.L., Cho Paik, M., Wick, I., Bennett, A., Jabado,
Rev. Gastroenterol. Hepatol. 9, 345–354. O., Hirschberg, D.L., Lipkin, W.I., 2011. Impaired carbohydrate digestion and transport
Novales-Li, P., 1996. Suramin exerts in vivo cytokine modulatory properties on and mucosal dysbiosis in the intestines of children with autism and gastrointestinal
splenocytes from experimental allergic encephalomyelitis-induced SJL mice: implica- disturbances. PLoS One 6, e24585.
tions for autoimmune disease therapy. Immunopharmacology 35, 155–162. Wood, J.H., Partrick, D.A., Johnston Jr., R.B., 2010. The inflammatory response to injury in
Novgorodov, S.A., Gudz, T.I., 2011. Ceramide and mitochondria in ischemic brain injury. children. Curr. Opin. Pediatr. 22, 315–320.
Int. J. Biochem. Mol. Biol. 2, 347–361. Xia, J., Lim, J.C., Lu, W., Beckel, J.M., Macarak, E.J., Laties, A.M., Mitchell, C.H., 2012. Neurons
Nyhan, W.L., 2005. Disorders of purine and pyrimidine metabolism. Mol. Genet. Metab. respond directly to mechanical deformation with pannexin-mediated ATP release
86, 25–33. and autostimulation of P2X7 receptors. J. Physiol. 590, 2285–2304.
Nyhan, W.L., James, J.A., Teberg, A.J., Sweetman, L., Nelson, L.G., 1969. A new disorder of Yang, Z., Ming, X.F., 2012. mTOR signalling: the molecular interface connecting metabolic
purine metabolism with behavioral manifestations. J. Pediatr. 74, 20–27. stress, aging and cardiovascular diseases. Obes. Rev. 13 (Suppl. 2), 58–68.
Oguma, T., Ito, S., Kondo, M., Makino, Y., Shimokata, K., Honjo, H., Kamiya, K., Kume, H., Yousefi, S., Gold, J.A., Andina, N., Lee, J.J., Kelly, A.M., Kozlowski, E., Schmid, I.,
2007. Roles of P2X receptors and Ca2+ sensitization in extracellular adenosine Straumann, A., Reichenbach, J., Gleich, G.J., Simon, H.U., 2008. Catapult-like
triphosphate-induced hyperresponsiveness in airway smooth muscle. Clin. Exp. release of mitochondrial DNA by eosinophils contributes to antibacterial defense.
Allergy 37, 893–900. Nat. Med. 14, 949–953.
Ohta, A., Nishiyama, Y., 2011. Mitochondria and viruses. Mitochondrion 11, 1–12. Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Nezasa, K., Tallman, M.N., Brouwer, K.L., 2006.
Ong, W.Y., Farooqui, T., Farooqui, A.A., 2010. Involvement of cytosolic phospholipase A(2), Integration of hepatic drug transporters and phase II metabolizing enzymes: mecha-
calcium independent phospholipase A(2) and plasmalogen selective phospholipase nisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur.
A(2) in neurodegenerative and neuropsychiatric conditions. Curr. Med. Chem. 17, J. Pharm. Sci. 27, 447–486.
2746–2763. Zhang, X., Hurng, J., Rateri, D.L., Daugherty, A., Schmid-Schonbein, G.W., Shin, H.Y., 2011.
Panossian, A., Wikman, G., 2009. Evidence-based efficacy of adaptogens in fatigue, Membrane cholesterol modulates the fluid shear stress response of polymorphonu-
and molecular mechanisms related to their stress-protective activity. Curr. Clin. clear leukocytes via its effects on membrane fluidity. Am. J. Physiol. Cell Physiol.
Pharmacol. 4, 198–219. 301, C451–C460.
Pastural, E., Ritchie, S., Lu, Y., Jin, W., Kavianpour, A., Khine Su-Myat, K., Heath, D., Wood, Zhou, R., Yazdi, A.S., Menu, P., Tschopp, J., 2011. A role for mitochondria in NLRP3
P.L., Fisk, M., Goodenowe, D.B., 2009. Novel plasma phospholipid biomarkers of inflammasome activation. Nature 469, 221–225.