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SHOCK, Vol. 45, No. 3, pp.

271281, 2016

Review Article
MITOCHONDRIAL FUNCTION IN SEPSIS

Nishkantha Arulkumaran, * Clifford S. Deutschman, Michael R. Pinsky, jj


Brian Zuckerbraun, Paul T. Schumacker, Hernando Gomez, jj!
Alonso Gomez, # ** Patrick Murray, and John A. Kellum jj!, on behalf of the
ADQI XIV Workgroup
*BloomsburyInstitute of Intensive Care Medicine, University Hospital London, UK; Department of
Pediatrics and Molecular Medicine, Hofstra-North Shore-Long Island Jewish School of Medicine, New
Hyde Park, New York; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania; Departments of Pediatrics-Neonatology, Cell and Molecular Biology and Medicine,
Feinberg School of Medicine, Northwestern University, Chicago, Illinois; jjDepartment of Critical Care
Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; !Center for Critical Care
Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania; #Academia Colombiana de Medicina
Critica (ACOMEC); **Division of Critical Care Medicine, Clnica Palermo, Bogota, Colombia; and

University College Dublin, Dublin, Ireland

Received 31 May 2015; first review completed 16 Jun 2015; accepted in final form 11 Aug 2015

ABSTRACTMitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy
adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like
sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long-term
morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to
extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness.
However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis
and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in
sepsis. This review should be used both as a summary source in placing mitochondrial physiology within the context of acute
illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide.
KEYWORDSConsensus, critical illness, mitochondria sepsis

Address reprint to Michael R. Pinsky, MD, Department of Critical Care Medi- INTRODUCTION
cine, University of Pittsburgh School of Medicine, 606 Scaife Hall, 3550 Terrace
Street, Pittsburgh, PA 15261. E-mail: pinskymr@upmc.edu The authors were tasked with developing five specific ques-
Authors Contributions: JAK, HG, AG, and PM all contributed to the preconfer-
ence and postconference e-mail discussions on this review, and reviewed and edited tions regarding mitochondrial function in sepsis within the
the final version of this manuscript. In addition, all contributed to the group breakout context of the Acute Dialysis Quality Initiative 14 (ADQI
sessions during the ADQI XIV conference. NA, CSD, and MRP created the first draft XIV) meeting held in Bogota, Colombia, in late 2014. The
of this manuscript, and NA, MRP, CSD, BZ, and PTS develop subsequent drafts and
approved the final manuscript. All authors (Appendix A) contributed to group authors presented these questions to the rest of the panel of
discussion and consensus. participants and from group discussions focused these ques-
ADQI XIV was funded by unrestricted educational grants from (in alphabetical
tions to address specific aspects of mitochondrial function.
order) Astute Medical Inc., Baxter Healthcare Corporation, Bellco S.R.L., Cyto-
sorbents Inc., Fresenius Medical Care, Spectral Diagnostics Inc., Toray Medical Co. Then off-line reviewed the literature and complied the answers
Ltd. to these questions which were vetted by all authors before
CSD and HG have no disclosures. NA received a research fellowship from the publication. What follows is the synthesis of this effort
Wellcome Trust. BZ has received research support from NIH (HL120877 and
HL074316). PTS has received research support from NIH (HL35440 and arranged under the heading of five key questions.
HL122062). MRP has received research support from Edwards Llifesciences and
NIH (HL07820, NR013912, H L120877, and HL074316). MRP has received
consulting fees from Masimo. JAK has received consulting fees from Abbott, METHODS
Aethlon, Alere, Alung, AM Pharma, Astute Medical, Atox Bio, Baxter, Cytosorb-
ents, venBio, Gambro, Grifols, Roche, Spectral Diagnostics, Sangart, and Siemens. Complete methods are available in the companion article to this series. (ref)
JAK has also received research grants from Alere, Astute Medical, Atox Bio, Bard, Briefly, we assembled a group of international experts with distinct clinical and
Baxter, Cytosorbents, Gambro, Grifols, Kaneka, and Spectral Diagnostics, and has scientific backgrounds; this group included physicians, specialists in critical
licensed technologies through the University of Pittsburgh to Astute Medical, care, anesthesiology, nephrology, surgery and emergency medicine, and basic
Cytosorbents, and Spectral Diagnostics. AG has received consulting fees from scientists with expertise in biology and physiology, who were recruited based on
Fresenius Medical Care. PM has received consulting fees from AM Pharma, Abbvie, their expertise in sepsis and organ dysfunction. The group consisted of 23
and FAST Diagnostics. He has also received research funding from Abbott, Alere, international experts from 5 continents. A set of questions were generated
and EKF Diagnostics. CD has received consulting fees from AM Pharma, Astute through mutual agreement, and we sought evidence to answer each question by
Medical, Baxter, Gambro, Spectral Diagnostics, GE, FMC, and ASAHI. searching the Cochrane Controlled Trials Register, the Cochrane Library,
The authors report no conflicts of interest. MEDLINE, and EMBASE from 1966 to present. Search terms for question
A complete list of authors is provided in Appendix A. regarding epithelial dysfunction are provided in Appendix B. Finally, we
DOI: 10.1097/SHK.0000000000000463 reviewed the evidence with the group and used the Delphi method to achieve
Copyright " 2015 by the Shock Society consensus.

271
Copyright 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
272 SHOCK VOL. 45, No. 3 ARULKUMARAN ET AL.

RESULTS stress. Studies have described evidence of mitochondrial dam-


age in critically ill patients and in experimental models of
Based on literature review and consensus among the work-
sepsis, but it is not clear whether this association represents
group members, the following key questions were considered:
organelle damage as a consequence of inflammation arising
from the response to infection, or whether the changes in
1. Are mitochondria the initiators, amplifiers, victims, or
mitochondria are etiologic in the development of cellular
innocent bystanders in the organ dysfunction in sepsis?
and organ dysfunction. Evidence suggests that signals from
2. To the extent that mitochondria are disrupted in sepsis, is the
healthy mitochondria can activate stress responses in cells, they
molecular mechanism related to bioenergetic function, oxy-
can activate transcription factors, including hypoxia-inducible
gen-dependent oxidative phosphorylation, cell death regu-
factor-1a (HIF-1a), NFkB, and p53, and they can initiate a
latory functions, biosynthetic, regulatory, or stress-related
suppression of metabolic activity mediated by activation of
signaling (e.g., reactive oxygen species [ROS]) functions?
adenosine monophosphate (AMP)-dependent protein kinase
What is the relationship between endothelial altered func-
(AMPK). Pathology samples from patients with critical illness
tion and organ function?
frequently reveal normal cellular morphology despite organ
3. To what extent does a disruption in mitochondrial dynamics
system dysfunction. This raises the question of whether signals
and homeostasis contribute to cellular and organ system
from mitochondria could be responsible for suppressing cel-
dysfunction in sepsis?
lular function, possibly as an adaptive mechanism to preserve
4. Is the trade-off between cell-adaptive and organ-mal-
cell survival. So, it is possible that in some cases mitochondria
adaptive responses a driver of organ dysfunction and long-
are damaged during the response to sepsis, that in other cases
term recovery in sepsis? Do organ-specific differences in
the generation of oxidants by mitochondria could induce or
this dichotomy determine outcome?
amplify tissue dysfunction, and yet in other cases the changes in
5. What are the mitochondria-based therapeutic targets and
mitochondria may represent a downstream marker of tissue
opportunities for intervention?
damage. Further studies are needed to determine the signifi-
cance of each of these roles in the septic patient.
Question 1. Are mitochondria the initiators, amplifiers, Question 2. To the extent that mitochondria are disrupted in
victims, or innocent bystanders in the organ dysfunction in sepsis, is the molecular mechanism related to bioenergetic
sepsis? function, oxygen-dependent oxidative phosphorylation, cell
Although a number of studies have assessed mitochondrial death regulatory functions, biosynthetic, regulatory, or stress-
morphology and function in experimental models of sepsis and related signaling (e.g., reactive oxygen species [ROS])
in critically ill patients, the relationship between mitochondrial functions?
function and organ system dysfunction is not fully elucidated.
Figure 1 shows the known roles mitochondria play during Bioenergetic function and oxygen-dependent oxidative
sepsis. Furthermore, Table 1 groups the cited studies into phosphorylation
groups based on their reporting on these various aspects of A functional alteration in O2 consumption (VO2)-related
mitochondrial health and function. Stresses associated with the metabolism may occur in sepsis (i.e., dysoxia). In resuscitated
systemic response to sepsis, including oxidative and nitrosative septic patients who have an increase in global O2 delivery and
stress, can contribute to mitochondrial dysfunction (115). adequate tissue perfusion, non-vital organ (e.g., skeletal
Conversely, mitochondria can function as a source of oxidant muscle) O2 tension remains elevated, suggesting a decrease

Mitochondrial Func!on and Sepsis


Metabolism and Cell Signaling
Oxida!ve phosphoryla!on and ATP produc!on
Primary source of VO2 and VCO2
Energy use priority: Na+ and Ca+2 transport, protein synthesis,
RNA and DNA replica!on
Intracellular Ca+2 homeostasis
Reac!ve oxygen and nitrogen genera!on cell signaling
Essen!al for normal cell func!on
Poten!al for harm if excessive (e.g. reperfusion injury)

Mitochondrial Injury and Repair


Apoptosis via intrinsic pathway: cytochrome c
Requires energy and is an!-inflammatory
Necrosis via membrane rupture
Pro-inflammatory release of mtDNA as PAMPS
Damaged mitochondria internally cleared: Mitophagy
Mitochondrial fusion, fission and biogensis
To maintain mitochondrial health quan!fied as membrane
poten!al ( by fusing damaged mitochondria with healthy
ones, pinching o damaged regions and synthesis of new
mitochondria

FIG. 1. Metabolism and cell signaling.

Copyright 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
SHOCK MARCH 2016 MITOCHONDRIAL FUNCTION IN SEPSIS 273
TABLE 1. Mitochondrial monitoring and functions
Clinical/ In vivo/ex
Reference Technique Measurement preclinical vivo Comment
Osbakken 1996 (1) NADH fluorometry NADH autofluoresence Preclinical In vivo The emitted light relates to the concen-
(450 nm) tration of the fluorescent compound
and represents changes in mitochon-
drial NADH, assuming constant total
NADH/NAD pool.
Stidwill 1998 (2)
Kraut 2004 (3) NADH (but not NAD")
autofluoresces in response
to 340 nm excitation light
Clavijo 2008 (4)
31
From 2011 (5) Magnetic resonance P-nuclear magnetic Preclinical In vivo Ratio of PCr to ATP is used to determine
spectroscopy (MRS) resonance is primarily level of metabolic stress
used, as it measures
changes in phosphocreatine
(PCr), ATP, Pi.
Weiss 2005 (6)
Kariman 1983 (7) Near infrared spectroscopy The Cu A center in the Preclinical In vivo When oxygen availability falls, the Cu A
to measure COX redox oxidized form of COX center becomes more reduced
state strongly absorbs in the
near-infrared spectrum
with a characteristic shape
and broad peak at 830 nm.
Guery 1999 (8)
Forget 2000 (9)
Cairns 1997 (10)
Mik (11) Endogenous delayed Mitochondrial oxygen tension Preclinical Ex vivo Protoporphyrin IX is endogenously pro-
fluoresce of duced in mitochondria and reacts
protoporphyrin IX strongly with oxygen
Protti (12) Spectrophotometry Mitochondrial respiratory Clinical Ex vivo Measured in homogenized in platelets
chain biochemistry and skeletal muscle
(complex activity)
Sjovall (13) High-resolution oxygraph Bioenergetic respiratory Clinical Ex vivo Measured in isolated intact in peripheral
Weiss (14) respirometry capacity, reserve and blood cells
uncoupling

Mitochondrial Change seen Time Organ/cell


function Role in health in sepsis course affected Possible effects in sepsis
Oxidative ATP production to maintain Decreased 2448 h Skeletal muscle Limitation of ATP, an extracellular DAMP
phosphoryaltion cellular bioenergetics
Decreased cellular function, possibly con-
serving intracellular resources for
future use.
Regulation of Intracellular signaling Unknown Unknown Multiple Upon depletion of ATP, Ca2 homeostasis
intracellular cannot be maintained, the MPT is
calcium levels induced, followed by cell death
ROS production Signaling (e.g., HIF-1a Increased Earlylate Multiple Enhanced oxidative burst and pathogen
upregulation in hypoxia) clearance
Toll-like receptor pathway activation
TNF receptor signaling to promote NF-kB
Protein nitration, DNA damage
Initiation of Mitochondria processes Increased Late T-lymphocytes Possible immunosuppression
apoptosis can activate apoptosis, mtDNA, released via exocytosis or pyrop-
an orderly, programmed tosis, is a potent DAMP
form of cell elimination
Mitophagy Damaged mitochondria Unknown
removed and replaced
Limits the accumulation of
depolarized mitochondria,
ROS generation and
activation of the NLRP3
inflammasome
Mitochondrial Creation of new and healthy Decreased Early Skeletal muscle During acute illness, skeletal muscle
biogenesis mitochondria (biogenesis) shows a 2-fold decrease in mitochon-
to meet cellular metabolic drial content in intensive care unit
energy demands patients with multiple organ failure.
Increased Late The course of sepsis and recovery is
characterized by an increment in mar-
kers of mitochondrial biogenesis and
mitochondrial number and density
(15).

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274 SHOCK VOL. 45, No. 3 ARULKUMARAN ET AL.

in local VO2 even though global VO2 may increase (16,17). The cells treated with ETC inhibitors cannot produce ROS and
mechanism underlying this reduction in regional O2 utilization failed to stabilize HIF-1a (36, 37). Cells lacking complex III
may be a consequence of changes in the mitochondrial respir- subunit cytochrome b were able to produce ROS, but could not
atory chain complexes. carry out oxidative phosphorylation, implicating the former in
Respiratory protein subunits and transcripts for complexes I HIF-1a stabilization (38). Hypoxia and the mtROS increases
and IV were downregulated in critically ill patients, with a more also increased VEGF transcription (39) and the contractile
prolonged recovery course and greater reduction in adenosine response of pulmonary arterial smooth muscle cells (40).
triphosphate (ATP) levels in eventual nonsurvivors (18,19).
Immune functions
Acute endotoxemia decreased cardiac muscle mitochondrial
O2 consumption and complex I activity, a change that was mtROS are potent initiators of the innate immune system.
associated with decreased ATP synthesis and ATP content (20), Inhibition of ETC complex I or III provoked a dose-dependent
whereas cecal ligation and puncture (CLP) models show increase in mtROS production and NLRP3 activation in a
decreased complex IV activity, a change associated with human THP1 macrophage cell line (41). NO downregulated
decreased contractility. During sepsis, there is a significant mtROS-induced NLRP3 inflammasome activity and was pro-
increase in nitric oxide (NO), mediated in part by increased tective in endotoxemia (42).
inducible nitric oxide synthase (iNOS) activity. The reaction of Macrophage clearance of bacteria involves phagocysis and
NO with superoxide generates peroxynitrite, a reactive nitro- ROS-mediated degradation of the pathogen. ROS in phag-
gen species (RNS) (21). Mitochondrial complexes I and IVare osomes, in turn, are produced by NADPH oxidase (NOX) and
susceptible to persistent inhibition from nitrosylation and by an increase in uncoupling protein 2 (UCP-2) expression
perhaps nitration ex vivo (22), and inhibition of NO ameliorates (43). mtROS also modulate Toll-like receptor (TLR) path-
the impaired mitochondrial respiration in endothelial cells ways. Depletion of mtROS by catalase overexpression
exposed to serum from septic patients (23). impaired clearance of intracellular organisms (Salmonella
In addition to mitochondrial complex expression and typimurium) (44). mtROS also function downstream in
activity, cytochrome c oxidase (CCO) was inhibited in a mouse TLR-activated signaling pathways such as tumor necrosis
model of sepsis induced by CLP. CCO inhibition was initially factor (TNF)-mediated activation of NF-kB (45).
competitive, but after 48 h became noncompetitive (24). Oxidative stress
Exogenous cytochrome c administered at 24 h after induction Superoxide is the primary oxidant produced by mitochondria
of sepsis restored cardiac mitochondria activity, increased respiratory complexes I, II, and III. In health, levels of super-
cytochrome oxidase kinetic activity, and improved cardiac oxide are contained by manganese superoxide dismutase
function (25). Exogenous cytochrome c 24 h post-CLP repleted (MnSOD), which is confined to mitochondria. NO reacts with
mitochondrial substrate levels for up to 72 h, restored myo- superoxide to generate the peroxynitrite and other RNS, (21)
cardial cytochrome oxidase activity, and improved both con- which are potent oxidizing agents and have been implicated in
tractility and survival (26). Caffeine administration 24 or 48 h protein nitration, DNA damage, and mitochondrial dysfunction
following CLP also improved CCO activity, restored cardiac in isolated mitochondria and in cells treated with serum from
contractility, and improved survival (27) septic patients (23, 46). Diaphragmatic and cardiac mitochon-
There are discrepancies in the literature with regard to drial O2" and H2O2 production were increased up to 3-fold
changes in complex activity in different muscle groups and during endotoxemia, and MnSOD activity showed a 2-fold
organs in sepsis (26,28) and endotoxemia (2931). This dis- increase in LPS-treated animals (47).
crepancy has been attributed to differences in the organs studied Mitochondria exposed to non-mtROS may become a source
(31), the time point of measurement, species involved, and of ROS themselves. Renal tubular cells increase their expres-
severity of illness. Importantly, changes in endotoxemia differ sion of iNOS and NADPH oxidase 4 (NOX-4) in response to
from those observed following CLP. Indeed, much of the LPS. This process can culminate in the cytosolic overexpres-
controversy surrounding the effects of sepsis on mitochondria sion of NO and superoxide anion, the primary RNS and ROS,
may reflect the inherent differences between LPS adminis- respectively (48), a positive feedback loop that may result in
tration, an acute inflammatory state, and more clinically dysregulation of mitochondrial function.
relevant models, such as CLP (3234). Treatment with antioxidants ameliorates organ injury in
experimental models of sepsis. Therapeutic agents tested include
Biosynthetic functions
N-acetyl cysteine (49) in hepatic oxidative stress and MITO-
Hypoxemia, which alters mitochondrial function, may be Tempo in renal injury (50). Limiting the production of perox-
associated with sepsis. The responses to hypoxia include the initrite abundance (with tetrakis-[1-methyl-4-pyridyl] porphyrin
upregulation of hypoxia-inducible factors, vascular endo- pentachloride, MnTMPyP, a peroxinitrite which prevents
thelium growth factor (VEGF), and glycolytic enzymes to decomposition catalyst or with NO with aminoguanidine
maintain ATP production. [AG], a NOS-2 inhibitor) (AG) prevented renal injury (51).
During normoxic conditions, constitutively expressed prolyl
hydrolyxase hydroxylates HIF-1a, which leads to proteosomal Cell death
degradation of HIF-1a (35). Hypoxia-induced mitochondrial ATP depletion, loss of mitochondrial membrane potential,
ROS (mtROS) are responsible for HIF-1a stabilization. Cells release of cytochrome C, and oxidative stress can lead to
with functional electron transport chain (ETC) deficiencies or apoptosis by altering the mitochondrial permeability transition

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SHOCK MARCH 2016 MITOCHONDRIAL FUNCTION IN SEPSIS 275

(MPT) (52). Upon depletion of ATP, Ca2 homeostasis cannot carry out this complex array of activities, it is critical to
be maintained, and the MPT is induced, followed by cell death maintain a population of viable mitochondria, typically defined
(53). Drugs such as cyclosporine A or carnitine inhibit MPT as maintenance of normal global mitochondrial membrane
opening (54). Lymphocyte apoptosis is associated with immu- potential (61).
neparesis and increased mortality among septic patients. The Several responses allow the mitochondrial network to adapt
mechanism behind increased lymphocyte apoptosis is multi- to stress and a loss of membrane potential. These include
factorial, though cell death via mitochondrial-mediated apop- mitochondrial fission and fusion, mitophagy, and mitochon-
tosis has been implicated. Apoptotic lymphocytes derived from drial biogenesis (6265).
septic patients contained active caspase 8 and caspase 9, Mitochondrial fission and fusion responses are dynamic
consistent with death occurring by both mitochondrial- and morphological changes that occur in the mitochondrial net-
receptor-mediated pathways (55). work (66). Fission is recognized as a coordinated process
whereby the mitochondrial network sequesters damaged
Temporal changes in mitochondrial function
elements of the mitochondria to a focal region, and this area
The relationship between sepsis-induced changes in mito- is then pinched off to maintain the overall health of the
chondrial function and organ dysfunction/recovery is time- network. Mitochondrial fusion can promote complementation
dependent and has important therapeutic implications. Alter- where a mildly damaged mitochondrion is assimilated into the
ations to respiratory protein subunits and transcripts occur healthier network, resulting in an overall maintenance of
within the first 24 h of ICU admission and correlate with membrane potential. These processes have been studied min-
eventual outcome (19). Skeletal muscle antioxidant reserves imally in the setting of sepsis. In a preclinical animal model
are reduced within 48 h of ICU admission, and are associated of sepsis (CLP), there was an abnormal balance of fission
with mortality (18). It remains unclear when these changes and fusion responses thought to contribute to cellular injury
begin to normalize. The production of mtROS probably occurs and apoptosis. The in vivo pretreatment with mdivi-1 (Drp1
early in sepsis, as it has a key role in innate immunity. It is inhibitor) significantly attenuated mitochondrial dysfunction
unclear when generation of mtROS ceases to be adaptive and and apoptosis in CLP (67).
becomes damaging. Lymphocyte apoptosis, although multi- Autophagy is a well-conserved, intracellular, catabolic proc-
factorial, is a late phenomenon (56). ess where proteins and organelles are isolated within a double
membrane vesicle (autophagosome), targeted to the lysosome
Monitoring mitochondrial health for degradation (6870). Specifically, mitochondrial autoph-
At present, monitoring of mitochondrial health is limited agy (or mitophagy) can consume damaged and dysfunctional
to experimental work. Promising real-time in vivo techniques mitochondria. Individual depolarized mitochondria, thought to
include NADH fluorometry, magnetic resonance spectroscopy, be separated from the network through fission, are targeted for
and near-infrared spectroscopy to measure COX redox state autophagosome formation and lysosomal degradation (71).
(57). Mitochondrial O2 tension can be estimated by measure- This process serves to eliminate the depolarized and damaged
ment of the phosphorescence decay time of sensors containing mitochondria that may otherwise produce oxidant stress within
protoporphyrin IX (58). These techniques have shown promise the cell, as well as release mitochondrial contents into the
in animal models of different shock states and warrant further cytosol or extracellular space, which can promote inflamma-
investigations in sepsis. tory and immune responses.
Mitochondria in circulating cells may provide insight into A number of clinical studies have illustrated increased
sepsis-associated temporal changes and how these changes autophagocytic signaling in multiple organs and tissues in
relate to recovery. Respiratory chain biochemistry in platelets sepsis (72). In addition, autophagy has been demonstrated in
is variably inhibited, with no convincing association with numerous animal models of sepsis or endotoxemia. Inhibition
either severity of illness or mortality (31). Reduced complex of autophagy in a CLP model resulted in increased apoptosis
activity in platelets is not a consistent finding (59), and may be and organ injury (73). Moreover, in a burn wound model in
time-dependent. Decreases in mitochondrial bioenergetic rabbits, insufficient autophagy was more pronounced in non-
reserve and increased uncoupling have been observed in surviving than in surviving animals, a finding that correlated
peripheral blood mononuclear cells obtained from septic chil- with impaired mitochondrial function and more severe organ
dren. A higher mononuclear mitochondrial membrane poten- dysfunction (74). In contrast, key substrates and controllers
tial on days 1 to 2 was associated with reduced organ injury by associated with mitochondrial fusion/fission or biogenesis were
day 7 (60). The application of mitochondrial bioenergetic not significantly different regarding survival status. Multiple
assessment in circulating cells requires further validation, preclinical studies have used nonspecific pharmacologic
and holds promise for monitoring illness progression and approaches that enhance autophagy and have demonstrated
therapeutic interventions. amelioration of organ injury (7577).
Question 3. To what extent does a disruption in mitochon- Mitophagy/autophagy blockade results in the accumulation
drial dynamics and homeostasis contribute to cellular and organ of depolarized mitochondria, and increased ROS generation
system dysfunction in sepsis? with an associated activation of the NLRP3 inflammasome
Multiple stressors have been shown to influence all known (78). Similarly, in vitro studies of macrophages stimulated with
mitochondrial functions, including oxidative phosphorylation, LPS and ATP led to ultrastructural damage of the mitochondria
as well as biosynthetic, regulatory, and signaling functions. To and increased cytosolic levels of mitochondrial DNA

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276 SHOCK VOL. 45, No. 3 ARULKUMARAN ET AL.

(mtDNA). Inhibition of autophagic signaling was manipulated Ischemic preconditioning is one such example. However,
and impaired; this process was exacerbated with augmented responses that are adaptive for survival of the individual cell
release of IL-1b and IL-18 (79). may be detrimental for tissue/organ function. Is the trade-off
Mitochondrial biogenesis refers to the process of the gener- between cell-adaptive and organ-maladaptive responses
ation of new mitochondria, which is a coordinated effort of a driver of organ dysfunction and long-term recovery in sepsis?
transcription and translation, involving both mitochondrial and Do organ-specific differences in this dichotomy determine
nuclear genomes. The generation of new mitochondria is outcome?
potentially critical to meet cellular metabolic energy demands The triggering of danger signals leads to the activation
and to fulfill other roles, including calcium homeostasis, main- of a number of protective responses (88). Danger, in turn,
tenance of cellular redox state, and cell signaling. In muscle may arise from a number of different stimuli. When confronted
biopsies of septic patients, the transcriptional coactivator of with even relatively mild hypoxia, protective mechanisms
mitochondrial biogenesis, PGC-1a, was significantly elevated decrease potential damage should the reduction in the oxygen
in survivors. Survivors also had higher muscle ATP levels and a supply become critical (89). Inflammation, sensed via the
decreased phosphocreatine/ATP ratio (80). In patients with binding of danger-associated molecular patterns or pathogen-
acute illness, skeletal muscle biopsies harvested from intensive associated molecular patterns to TLR receptors, is known to
care unit patients with organ dysfunction demonstrated a 2-fold initiate protective mechanisms via the MyD88/TRADD/NF-kB
decrease in mitochondrial content (81). In preclinical models of and JAK1/STAT3 pathways (90). Responses linked to mech-
sepsis, the onset of mitochondrial biogenesis has been shown to anical deformation may be the result of nuclear compression
correspond to the restoration of normal mitochondrial oxidative (91). It appears that the cellular response to these danger
respiration (82). The course of sepsis and recovery is charac- signals is modulated by mitochondria.
terized by an increment in markers of mitochondrial biogenesis Responses to hypoxia lie, in part, in the terminal cytochrome
and mitochondrial number and density (83). oxidase, complex IV, which binds oxygen, and thus can respond
Biogenesis and autophagy have been linked in several pre- to critical hypoxia (89). Interestingly, potentially protective
clinical models of sepsis. One study suggested that mitochon- responses are activated at O2 concentrations that do not com-
drial biogenesis was dependent on an autophagy and mtDNA/ promise the synthesis of ATP: complex IV continues to con-
Toll-like receptor 9 (TLR9) signaling (83). sume oxygen at a constant rate even as the O2 levels decrease.
Another study using an endotoxemia model demonstrated a Therefore, diminished ATP levels cannot be responsible for
simultaneous increase in mitochondrial biogenesis and triggering protective responses until the oxygen supply
mitophagy through the actions of Sirt1, Pink1, and Parkin. becomes critically low. Electron transport, however, is in flux
This was associated with lower levels of lung and mitochon- even when oxygen consumption and ATP generation are main-
drial injury, as well as reactive oxygen species and improved tained. Even mild hypoxia can limit the reoxidation of cyto-
survival (84). chrome c. As the cytochrome c pool becomes progressively
In addition, it is important to consider the temporal aspects of more reduced, the capacity to absorb electrons is limited and
mitochondrial functions and dynamics as they relate to the the transfer of electrons to complex IV becomes impaired.
stage of the disease process, specifically infection and sepsis. Electron transfer from complex III is limited with a resultant
The biology inciting sepsis involves a complex interplay of increase in the generation of ROS: limiting the activity of
microorganisms and host/host responses. It has been hypoth- complex IV increases electron density at complex III and
esized that a decrease in mitochondrial function, which may results in enhanced generation of O2" (89). The generation
lead to or coincide with a loss of critical cell-specific functions, of ROS has also been implicated in cytokine- and deformation-
may be an adaptive response that prevents cell death to allow mediated signaling. Proinflammatory cytokines such as TNF,
for eventual recovery (8587). Downregulation of certain IL-1 (via TLR-MyD88-mediated NF-kB activation), and IL-6
mitochondrial functions, including oxidative phosphorylation, (via JAK-1/STAT3 activation) accelerate ROS production and
may be aimed at limiting the production of ROS which would augment the release of Ca2 and proapoptotic proteins
otherwise damage cells further. It has been hypothesized that (90, 92, 93). These processes damage mitochondria, accelerat-
these responses are akin to cellular estivation (i.e., hibernation), ing mitophagy and activating NRF-2, HO-1, AMPK, and SIRT-
allowing for a slowing down of energy utilizing processes. 1. In addition, these stimuli activate nuclear paradigms that
However, temporally there must also be restitution processes promote biogenesis (90). A rising ratio of AMP to ATP
(including biogenesis) to allow for eventual recovery. indicates energy supply limitations, with AMPK-mediated
The complex interplay of these mitochondrial dynamics and blockade of ATP-consuming processes, especially mitogenic
homeostasis responses is critical to cell biology in response to pathways controlled by mTOR (94). Perturbations of cell
stress. Further studies in preclinical models and in patients architecture, such as those accompanying mechanical defor-
highlighting the relationship and temporal aspects of these mation, affect membrane potential by altering mitochondrial
processes are necessary. This potentially will guide the devel- volume (91), an effect that likely results in ROS liberation
opment of targeted therapies to harness adaptive and minimize (95, 96).
maladaptive responses. In addition to direct damage to membranes via lipid
Question 4. Diverse cells respond to stresses (e.g., hypoxia, peroxidation, enhanced ROS production activates HIF-1a
cytokines, mechanical deformation) by activating mitochondria- (97, 98). HIF-1a is a heterodimeric protein transcription
dependent signals that trigger cellular protective responses. factor that, under unstressed conditions, is inactive. Cellular

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SHOCK MARCH 2016 MITOCHONDRIAL FUNCTION IN SEPSIS 277

abundance of the active heterodimer is low because continu- the generation of metabolic intermediates that affect intracellu-
ous hydroxylation of proline residues targets the HIF-1a lar signaling pathways and thereby alter cell function. Finally,
subunit for proteosomal degradation (97, 99). ROS prevent metabolic reprogramming can alter the availability of cofactors
degradation, stabilizing the heterodimer and facilitating involved in post-translational modifications of proteins. This
HIF-1a-mediated transcription (98). can affect signaling pathways and also induce epigenetic
One consequence of the activation of a danger response changes by affecting the post-translational modification of
pathway in cells is a reduction in cellular activity beyond the histone proteins. Mitochondria are centrally involved in cellular
level of maintenance of basic cellular integrity. Under this metabolism, through their energy production, ROS generation/
paradigm, cells suppress some energy-dependent activities in oxidant signaling, and their ability to interconvert biomolecules
favor of those that are essential for cell survival (100). through the tricarboxylic acid (TCA) cycle (107). The meta-
Examples abound in patients with sepsis and under other bolic disruptions observed in tissues during sepsis show sim-
circumstances. The most obvious example is the sepsis-induced ilarities to the patterns observed in other diseases, so it is
loss of cardiomyocyte contractility. High levels of pharmaco- possible that treatments for those conditions might also be
logical support are required to support cardiac ejection, and useful in sepsis.
vascular tone yet cell death is rare. Cardiac performance is For example, increases in circulating lactate are common in
analogous to that seen following myocardial infarction, where septic patients, even in the apparent absence of tissue hypoxia
the remaining cardiomyocytes hibernate, presumably to (108). This may be the result of cytokine or catecholamine
allow recovery (87). A similar response in liver is reflected signaling, and some studies have observed a correlation
in low levels in the synthesis of excreted proteins and impaired between the degree of lactatemia and the severity of sepsis,
transformation of both exogenous and endogenous (i.e., bilir- the outcome, and the response to treatment. This shift to aerobic
ubin) toxins (101). In pulmonary cells, this phenomenon has glycolysis resembles the Warburg effect seen in many cancers
been called hypoxic conformance and is characterized in (109). The similarities in altered metabolism in cancer and in
part by internalization, and thus inactivation, of ATPase-linked sepsis raise the question of whether interventions that correct
transmembrane pumps (102). The net result is a failure to clear metabolism toward a normal phenotype could be useful thera-
fluid from the alveolar spaces, resulting in pulmonary edema. peutically. Clearly, uncontrolled cell proliferation as seen in
A number of sepsis-induced processes have been attributed cancer is not evident during sepsis. Nevertheless, the increased
to anti-inflammation or immunosuppression (103). How- glycolysis in cancer cells is important for channeling glycolytic
ever, these changes might rather reflect leukocyte hiber- intermediates into the pentose phosphate pathway, which gen-
nation. Similarly, muscle catabolism is part of the erates NADPH needed for cellular antioxidant activity (110).
inflammatory process and, under balanced conditions, is fol- Inhibition of NADPH synthesis causes lethal oxidant stress in
lowed by anabolism (104, 105). However, decreased catabo- tumor cells, and the augmented glucose utilization in sepsis
lism accompanied by failed or insufficient anabolism might may represent a physiological attempt to manage oxidant stress.
reflect muscle hibernation. Presently, it is not clear whether the increase in aerobic
Cellular hibernation in renal epithelial cells would be con- glycolysis in sepsis is a marker of inflammation or an upstream
sistent with the low levels of cell death observed in septic mediator of cellular dysfunction. More information is therefore
patients with AKI (106). With rapid recovery, the net effect needed to understand whether throttling the glycolytic flux
would be preservation of renal function for the recovery phase. would confer protection, or alternatively exacerbate the con-
However, prolonged inhibition of energy-requiring functions, dition by undermining antioxidant capacity. In either case,
such as reduced transcellular electrolyte transport, impaired limited therapeutic options for modifying aerobic glycolysis
secretion of potential toxins, and limited generation of essential are currently available.
circulating ions such as bicarbonate and ammonium, would Septic patients frequently develop hyperglycemia. Insulin
diminish survival. It is possible that early institution of current can be used to control blood glucose in septic patients although
or future therapeutic approaches could prevent the systemic this carries the risk of inducing hypoglycemia (111). The
effects that would result from a reduction in available energy antidiabetic drug metformin decreases gluconeogenesis in
resources with a reprioritization of renal function. Thus, it is the liver and ameliorates hyperglycemia by lessening hepatic
essential that a method for determining when limited renal glucose release. This effect is mediated by its inhibition of
activity becomes maladaptive be developed. mitochondrial complex I, causing a decrease in ATP that
Question 5. What are the mitochondria-based therapeutic activates AMPK. AMPK is a master regulator of cellular energy
targets and opportunities for intervention? flux; it inhibits anabolic, energy-consuming processes while
In patients with sepsis, alterations in cellular metabolism can promoting catabolic, energy-producing pathways. In sepsis,
develop as a consequence of inflammation, cytokine signaling, AMPK activation might confer protection by attenuating
tissue hypoxia, catecholamine stimulation, altered insulin sig- inflammation and inflammatory cytokine expression, by aug-
naling, and other factors. Disordered metabolism in sepsis can menting glucose uptake, or by suppressing the effects of
disrupt glucose metabolism, resulting in augmented glycolytic inflammation on endothelium. AMPK is activated by hypoxia-
flux and increased lactate production, even in the absence of or ischemia-induced bioenergetic crises that decrease ATP
cellular hypoxia. It can also disrupt lipid metabolism, resulting levels. However, it is also activated by mild hypoxia which
in the generation of inflammatory lipid mediators that contrib- causes release of mtROS signals (112). AMPK has been shown
ute to organ dysfunction. Altered metabolism can also result in to protect against organ failure and inflammation in mouse

Copyright 2015 by the Shock Society. Unauthorized reproduction of this article is prohibited.
278 SHOCK VOL. 45, No. 3 ARULKUMARAN ET AL.

models of experimental sepsis (113). Therefore, manipulation DMAT inhibitor, 5-aza 2-deoxycytidine, has been used for
of AMPK using available drugs might be therapeutic in sepsis. the treatment of myelodysplastic syndromes and leukemias.
As in cancer, metabolic reprogramming in sepsis may affect Interesting emerging data suggest that this drug may confer
tissue function by promoting epigenetic changes that shape protection against acute lung injury in a rodent sepsis model.
gene expression during acute illness and long after recovery. Many cancer chemotherapeutic agents induce significant
Key mechanisms of epigenetic change involve post-transla- tissue injury in the heart, lungs, kidneys, and the central nervous
tional modifications to histone proteins in chromatin. The most system, and would be unsuitable for the treatment of sepsis.
common modifications involve the methylation or acetylation However, the examples presented above suggest that some
of lysine residues on histones. These modifications can increase agents used for the treatment of diverse disorders might be
or decrease expression of genes by altering the accessibility of useful in the treatment of acute sepsis. Clearly, additional
specific sites to transcription factors, by creating DNA binding studies are necessary to explore these possibilities.
sites on chromatin, and by facilitating proteinprotein inter-
actions that modify transcriptional activation or repression. In ADQI XIV Workgroup
sepsis, it is well-established that extracellular signals induced Nishkantha Arulkumaran
by the inflammatory cytokines can alter cellular function. Vincenzo Cantaluppi
Similarly, intracellular metabolic reprogramming may lead Lakhmir S. Chawla
to epigenetic changes through alterations in the availability Daniel de Backer
of cofactors needed for the post-translational modification of Clifford S. Deutschman
histone proteins. In cancer and other diseases, epigenetic Mitchell P. Fink
modifications to histones proteins can alter the cellular phe- Stuart L. Goldstein
notype in terms of proliferation, survival, and metastatic Hernando Gomez
behavior. Conceivably, altered metabolic pathway functions Alonso Gomez
in sepsis and critical illness could induce epigenetic modifi- Glenn Hernandez
cations and thereby shape organ system function during the Can Ince
disease and long after. John A. Kellum
Lysine residues on histone tails are acetylated by histone John C. Marshall
acetyltransferases (HAT) that use acetyl CoA, an important Philip R. Mayeux
metabolic intermediate, as a cofactor. In mitochondria, acetyl Patrick Murray
CoA generated by pyruvate dehydrogenase is condensed with Trung C. Nguyen
oxaloacetate to generate citrate in the TCA cycle. Citrate can Steven M. Opal
then be exported to the cytosol where acetyl CoA and oxaloa- Gustavo Ospina-Tascon
cetate are released by ATP citrate lyase. Thus, the mitochondria Didier Payen
function as an important source of acetyl CoA needed for HAT Michael R. Pinsky
activity. Reversal of acetylation is achieved by histone deace- Thomas Rimmele
tylases (HDAC), some of which (sirtuins and class III) use Paul T. Schumacker
NAD as a cofactor. Metabolic reprogramming in sepsis and Brian S. Zuckerbraun
cancer can alter NAD levels in the cytosol as a consequence of
altered glycolytic and/or mitochondrial function, thereby alter-
ing the availability of this cofactor for HDAC activity. HDACs SEARCH TERMS
also regulate acetylation of cytosolic proteins, and can thereby Mitochondria, sepsis, inflammation, mitophagy, apoptosis,
affect cells signaling and protein trafficking. HDAC inhibitors biogenesis.
have long been used as psychotropic medications, and recently
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