Inflammation Research (2021) 70:379–387

https://doi.org/10.1007/s00011-021-01447-0 Inflammation Research

REVIEW

Sepsis‑induced myocardial dysfunction: the role of mitochondrial

dysfunction
Hang Yang1 · Zhaocai Zhang2

Received: 18 August 2020 / Revised: 18 February 2021 / Accepted: 22 February 2021 / Published online: 8 March 2021
© The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021

Abstract
Introduction Sepsis-induced myocardial dysfunction (SIMD) is a condition manifested by an intrinsic myocardial systolic
and diastolic dysfunction during sepsis, which is associated with worse clinical outcomes and a higher mortality.
Materials and methods Several pathophysiological mechanisms including mitochondrial dysfunction, abnormal body
immune reaction, metabolic reprogramming, excessive production of reactive oxygen species (ROS), and disorder of calcium
regulation have been involved in SIMD. Mitophagy has potential role in protecting myocardial cells in sepsis, especially in
survivors.
Conclusion In the current review, we focus on the role of mitochondrial dysfunction and other mitochondria-related mecha-
nisms including immunologic imbalance, energetic reprogramming, mitophagy, and pyroptosis in the mechanisms of SIMD.

Keywords Sepsis-induced myocardial dysfunction · Mitochondrial dysfunction · Lactate · Immunosuppression

Introduction [6], high-mobility group box 1 (HMBG1) [7], and activated

SIMD is defined as a reversible myocardial dysfunction
characterized by typical ventricular dilation, decreased
ventricular contractility, and/or reduced response to vol-
ume resuscitation. SIMD is a major complication of sepsis
and has a negative impact on patients’ survivals [1, 2]. Evi-
dence suggests several mechanisms and signal pathways.
Mitochondrial dysfunction has become a serious concern,
including oxidative phosphorylation, production of ROS,
reprogramming metabolism of energy [3], and mitophagy
[4]. And body’s immune reaction changes may also play a
potential role in SIMD. Previous research has also shown
other factors are associated with SIMD including altered
epigenetic modification [5], myocardial depressant factors,
pathogen-associated molecular patterns (PAMPs), host-
produced danger-associated molecular patterns (DAMPs)
* Zhaocai Zhang
2313003@zju.edu.cn
1
Department of Gastroenterology, West China Hospital,
Sichuan University, No. 37, Guo Xue Xiang, Wu Hou
District, Chengdu 610041, China
2
Department of Critical Care Medicine, Second Affiliated
Hospital, School of Medicine, Zhejiang University, Jiefang
Road No. 88, Hangzhou 310000, Zhejiang province, China
complement components [8]. In addition, the role of pro-
inflammatory cytokines, decreased coronary perfusion, and
altered microcirculation in the presence of severe hypoten-
sion during sepsis can also lead to myocardial hypoxia and
dysfunction [9, 10]. In this article, the potential role of mito-
chondria in the mechanism of SIMD will be reviewed.
Mitochondrial dysfunction
Changed ultrastructure and structural protein
of mitochondria
Mitochondrial permeability transition pore (mPTP) is pro-
posed as a high-conductance channel of the almost imper-
meable inner mitochondrial membrane (IMM) [11]. Physi-
ologically, it serves as a rapid mitochondrial efflux channel
for ROS and ­Ca2+ via a transient opening [12]. Its abnormal
opening can increase the IMM permeability and change the
membrane potential of the mitochondria, leading to a reduc-
tion of the electrochemical transmembrane gradient, uncou-
pling of oxidative phosphorylation, increasing production of
ROS, and decreasing production of ATP [13]. Furthermore,
the c-ring of the F1F0-ATP synthase has been demonstrated
as a component of mPTP and might directly influence ATP

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synthase [14]. In addition, mPTP is tightly associated with
cell apoptosis [15]. When outer mitochondrial membrane
(OMM) ruptures, N-formyl peptides, ATP, and cytochrome
C are released, and cellular ATP is depleted after the irre-
versible opening of mPTP [16, 17], which can be initiated by
calcium retention, a central stimulator. Besides the calcium
concentration, pH, ROS, nitric oxide (NO) production in
excess, peroxynitrite formed from NO can affect the func-
tion of mPTP [18]. An mPTP opening was observed in the
swelling mitochondria [16]. Multiple mPTP inhibitors have
demonstrated efficacy in preclinical disease models [19].
However, although mPTP is involved in cell damage and
death, SIMD lacks cell necrosis or apoptosis probably asso-
ciated with the severity of sepsis. This also indicates that the
Fig. 1  Summary of the possible mechanisms involved in SIMD,
including dysregulation of calcium, dysfunction of mitochondria,
reprogramming of the energy metabolism, overproduction of ROS,
opening of mPTP, and mitophagy. During sepsis, energy metabo-
lism is switched to aerobic glycolysis, the same as the pathway of
hypoxia that has been suggested as a strong inductor of mitophagy.
AMPK: AMP-activated protein kinase; cAMP: 3′-5′-cyclic adeno-
sine monophosphate; CAT: catalase; C1: carrier 1; C2: carrier 2;
Cyt C: cytochrome c; ECC: excitation–contraction coupling; HIF-
1a: hypoxia-inducible factor-1a; GPCR: G protein-coupled receptor;
GPx: glutathione peroxidase; LTCC: L-type calcium channels; MCU:
13
H. Yang, Z. Zhang
opening of mPTP is properly functioning, when myocardial
cells suffer from deteriorating sepsis (Fig. 1).
Regulation and dysregulation of mitochondrial
calcium in sepsis
The dysregulation of mitochondrial calcium was observed
in the case of sepsis. In myocardial cells, the homeostasis
of calcium is both cytoplasmic and mitochondrial. Mito-
chondrial ­Ca2+ channels in IMM include mitochondrial
­Ca2+ uniporter (MCU), mitochondrial ryanodine recep-
tor (mRyR), mPTP, mitochondrial Na+/Ca2+ exchanger
(mNCX) [20], and H ­ +/Ca 2+ exchanger (mHCX) [13].
MCU is dependent on the IMM potential, associated with
mitochondrial calcium uniporter; MPC: mitochondrial pyruvate car-
rier; mPTP: mitochondrial permeability transition pore; mTOR:
mechanistic target of rapamycin; N ­ AD+: nicotinamide adenine dinu-
cleotide; PAMPs/DAMPs: pathogen/damage-associated molecular
patterns; PARP: poly (ADP-ribose) polymerase; PDC: pyruvate dehy-
drogenase complex; PDKs: pyruvate dehydrogenase kinases; PI3K:
phosphatidylinositol 3-kinase; RIP3: receptor‑interacting serine/thre-
onine kinase 3; RyR: ryanodine receptors; SERCA: sarcoendoplasmic
reticulum Ca2+ ATPase; SOD: superoxide dismutase; TAC: tricarbo-
xylic acid cycle; TLR: Toll-like receptor; TNF: tumor necrosis factor;
VDAC: voltage-dependent anion channel
Sepsis‑induced myocardial dysfunction: the role of mitochondrial dysfunction 381
the matrix calcium and extramitochondrial ­Ca2+ concen-
tration. It contributes to oxidative phosphorylation and
activates the dehydrogenase of the TCA cycle to increase
the production of NADH for electron transport chain
(ETC) and ATP generation [21]. Voltage-dependent anion
channel (VDAC), a part of mPTP, provides a pathway for
­Ca2+ and metabolite transportation across OMM [22]. In
addition, approximately 20% of the mitochondrial surface
has been found to be close to the endoplasmic reticulum
in mammalian cells generating high C ­ a2+ microdomains,
termed as mitochondria-associated membranes (MAMs)
[23]. When the calcium-induced calcium release (CICR)
is activated by autonomic nervous system, a considerable
amount of calcium is released from ER via RyR, and cal-
cium flows into mitochondria through VDAC in OMM
[24]. Thereafter, sarcoplasmic reticulum ­C a 2+ ATPase
(SERCA) reabsorbs calcium to prevent cytoplastic over-
load, which is a determinant of calcium homeostasis.
Tumor suppressor p53 localized in ER can interact with
SERCA and exert its pro-apoptotic function by regulating
the transporting calcium into mitochondria [25]. An anti-
apoptotic member of the Bcl-2 family has been suggested
to interact with VDAC and protect cells from death by
limiting the transfer of C­ a2+ signals to mitochondria [26,
27]. Although calcium overload has been widely shown in
septic models which can be via C ­ a2+ channels mentioned
above, little necrosis has been observed in survivors,
compared with autophagy which are mediated by mito-
chondria. In mice, autophagy could play a protective role
against pressure-overload-induced mitochondrial dysfunc-
tion and heart failure via regulating Drp1 [28]. Upregu-
lation of autophagy via activation of SIRT1 could pro-
tected against SIMD [29]. Therefore, calcium overload and
necrosis may occur via ­Ca2+ channels mentioned above,
but not be the first and appropriate choice in survivors, as
the balance of apoptosis via apoptotic member interacting
with ­Ca2+ channels would be kept and autophagy would
be activated to protect mitochondria and myocardial cells
(Fig. 1).
Production and over‑production of mitochondrial
ROS
Sepsis can cause cardiac mitochondrial damage by increas-
ing oxidative stress and decreasing antioxidant defense,
causing mitochondrial ROS (mtROS) overproduction, fur-
ther mitochondrial functional deficiency, and structural rup-
ture due to direct oxidation. The scavenging of mtROS can
be achieved via enzymatic and non-enzymatic antioxidants,
such as glutathione peroxidase (GPx), catalase (CAT), and
superoxide dismutase (SOD). The accumulation of ROS can
lead to more electron leakage after damaging ETC, activa-
tion of poly ADP-ribose polymerase (PARP) after damaging
mtDNA [30], and opening of mPTP [31]. It can also cause
decreasing oxygen consumption and ATP production [32],
decreasing mitochondrial membrane potential and activity,
and decreasing expression of respiratory complexes [33].
Evidence suggested the suppression of mtROS protected car-
diac mitochondria, attenuated inflammation, and improved
heart function in the animal models of sepsis. The electron
leakage depends on the ATP demand [34]. Some models
showed that mitochondria-targeted ROS scavengers such
as mitochondrial Q was cardioprotective [35]. The anaes-
thetic agent propofol manifested its cardioprotective effect
by scavenging free radical [36]. Clinical therapeutic effects
of some typical antioxidants such as vitamin C, vitamin E,
and SOD were conflicting. Vitamin B and C combined with
corticosteroid in sepsis has been suggested as a promising
therapy but currently lacks robust evidence to support its
widespread use [37]. NOX inhibitors were also indicated to
selectively attenuate disease-related ROS formation without
altering physiological signaling ROS [38]. The myocardial
cells switch their metabolism to aerobic glycolysis leading
to the reduction of the ATP generation [3]. It is reasonable to
hypothesize that glycolysis increases and oxidative phospho-
rylation decreases, contributing to decreasing production of
mtROS and reduce the damage from mtROS to mitochondria
and cells [39]. Glycolysis can be initiated by hypoxia dur-
ing sepsis. Theoretically, TCA cycle will decrease and the
production of mtROS will correspondingly decrease. Fur-
ther in this way, damage from mtROS to mitochondria will
be alleviated, especially ETC which is prone to mtROS. It
may also indicate self-protection of mitochondria is initi-
ated when exposed to sepsis, as continuous impairment of
mitochondria including ETC can induce NLRP3 inflamma-
some [40]. On the other hand, there is a tightly association
between mitochondrial energy metabolism and mitochon-
drial dynamics. As it was known that, LPS-induced M1
macrophages could reprogram their energetic metabolism
to glycolysis during infection to afford the energy need to
kill pathogens and survive, similar to cancer cells [41]. The
metabolic reprogramming in mitochondria is also associ-
ated with altered mitochondrial morphology [42]. Mitochon-
drial dynamics can control T cell fate through metabolic
programming. Mitochondrial fission will facilitate glycolysis
and mitophagy which eliminate impaired fragmented mito-
chondria via fission [43] (Fig. 1).
Mitophagy and its potential role
in protecting myocardial cells in sepsis
Mitophagy is an important method to remove damaged
mitochondria by isolating dysfunctional mitochondria from
healthy ones by double-membrane vesicles called autophago-
somes and subsequently delivering autophagosomes to
13
382
lysosomes. It protects body cells against septic stress [44],
which can be strongly activated by mitochondrial depolari-
zation before damage triggers necrosis [45]. The canonical
signal pathways are PINK1/Parkin and DJ-1 pathway. ROS
induced mitochondrial damage might be a necessary activa-
tor to mitophagy [46]. In the pathway, PINK1 kinase accu-
mulates on the mitochondria and phosphorylates mitofusin 2
(MFN2). Parkin E3 ligase binds phosphorylated MFN2 and
localizes to the mitochondria [4]. The ubiquitination of sev-
eral proteins on mitochondrial surface and various adapter
proteins, including MFN1, MFN2, optic atrophy protein 1
(OPA1), and VDAC, are associated with the mitophagy, ulti-
mately facilitating the elimination of the mitochondrial con-
tent [47, 48]. Moreover, VDAC was shown to be necessary
for the PINK1/Parkin-directed mitophagy of damaged mito-
chondria [49]. LPS injection significantly downregulated
MFN1, MFN2, and OPA1, which are primary regulators of
mitochondrial fusion. However, excessive mitochondrial fis-
sion and mitophagy can compromise the metabolic capacity
of a cell [50]. During sepsis, mitochondrial dysfunction is
characterized with calcium dysregulation, overproduction
of ROS, opening of mPTP, and a final loss in mitochondrial
membrane potential, which induces cell death if progressive.
But if mitophagy occurs in myocardial cells instead of the
above processes, myocardial cells will avoid massive death,
benefiting cell survival.
On the other hand, the opening of mPTP is pivotal to the
fate of mitochondria and cells. And from the content men-
tioned above, it is not the first choice of survival cells. There-
fore, the reason to keep its functional opening is of interest.
Cytochrome C can be released after mPTP opening to induce
apoptosis. The cardiolipin located in IMM is required for the
dissociation of cytochrome C after its oxidation, as activated
calpain 1 cleaves Bid, inducing cytochrome C release [51].
Therefore, oxidation resistance is critical for cell survival.
mGPx4, is a kind of GPx4 transported to mitochondria after
synthesis in cell nucleus. It can suppress the peroxidation of
cardiolipin in mitochondria and inhibit the dissociation of
cytochrome C from IMM in apoptosis [52]. Furthermore,
mGPx4 catalyzes the decomposition of hydrogen perox-
ide or organic hydroperoxides using the reduced form of
glutathione as an electron donor [53]. Meanwhile, mGPx4
can inactivate Adenine nucleotide translocator (ANT), a
component of mPTP, to inhibit the opening of mPTP and
the opening of VDAC [54]. If the expression of GPx4 is
upregulated when a myocardial cell is exposed to sepsis,
the pathway of cell death including apoptosis and necrosis
is suppressed, and then, the mitophagy is chosen to begin.
However, cardiac mGPx4 decreases after sepsis, and the
activity of GPx4 falls to 70% after 12–24 h [55]. As mGPx4
is reductive and protective, the more reasonable explana-
tion for the “contradiction” is that the expression of mGPx4
is not always increasing, and also has its compensational
13
H. Yang, Z. Zhang
scope. Further research on the GPx4 expressed in a myocar-
dial cell is required, especially focusing on the correlation
between mitophagy and expression of GPx4 (Fig. 1).
Immunosuppression and pyroptosis in SIMD
Sepsis is a result of uncontrolled primary and secondary
infection under the condition of abnormal immunity [56].
It will further result in tissue damage, cellular compromise,
and molecular dysregulation, further initiating organ dys-
function and multiorgan failure [57]. In SIMD survivors,
necrosis of myocardial cells is little, which indicates the
damage from host immune cells and pathogens is not inten-
sive enough to induce necrosis, compared with not massive
apoptosis. Therefore, there would be a balance between host
immunity and pathogens during SIMD as immune cells can
still not clear the pathogens. Immunosuppression involving
innate immune and adaptive immunity has always been seen
in sepsis because of lymphocyte apoptosis via caspases 8/9
and finally caspase 3 by both mitochondrial-mediated and
receptor-mediated pathways [58, 59]. A decreased produc-
tion of inflammatory cytokines has also been demonstrated
such as decreased TNF, IL‑1α, IL‑6, and IL‑12 [60], inter-
feron γ (IFN γ) [61], and macrophage colony-stimulating
factor (GM-CSF). Protein expressed on the lymphocyte
also change. And these changes include the downregula-
tion of CD127 and Bcl-2, and the upregulation of inhibitory
receptors [62]. Sepsis can also induce a subset of neutrophils
with suppressive properties, as these neutrophils produce
large amounts of the immunosuppressive cytokine IL-10
during sepsis. The most dominant function of macrophages
is the phagocytosis of both pathogens and apoptotic cells.
Macrophages’ clearance of innate immune cells can also be
weakened by an increasing production of IL-10 from neutro-
phils [63] and pyroptosis, a type of programmed cell death,
via caspases 11 after detecting the LPS invasion in cytosol
[64]. Pyroptosic cell can be finally uptake by the neutrophil
in response to phagocytosis, which might be able to resist
pyroptosis in response to some inflammasome activators
[65]. During sepsis, neutrophil apoptosis is delayed in con-
trast to the lymphocytes undergoing accelerated apoptosis
[66], which indicates that (1) neutrophils may last longer
in sepsis than lymphocytes, (2) the clearance function of
lymphocytes is actually impaired, and (3) increasing pyrop-
tosis exists. In addition, Gpx4 expressed by cells from the
myeloid lineage plays a major role in attenuating lipid perox-
idation, inflammasome activation, and pyroptotic cell death
in the context of sepsis. The depletion of Gpx4 results in
increased septic lethality [67]. GPx4 may be a requisite gate-
way to pyroptosis at least via caspases 11 [53]. Therefore,
pyroptosis will take more account of the programmed cell
death of innate immune cells. In this way, a balance can be
Sepsis‑induced myocardial dysfunction: the role of mitochondrial dysfunction 383

achieved. Although immune cells are suppressed, pathogens
can still be swallowed in their cytoplasm which can further
decrease the damage from both immunity and pathogens.
This “balanced” status of survivors can be ended with the
improvement of host immunity. And continuous increase of
pyroptosis means the host immunity is still in suppressed
and pathogens’ virulence is not attenuated, indicating poor
outcomes. It was also demonstrated that increased LPS-
induced pyroptosis and the inhibition of autophagy by highly
expressed ZFAS1 could aggravate the progression of SIMD
in the in vivo and in vitro model [68] (Fig. 2).
Enhancing body immunity benefits SIMD
Some basic research related to the enhancement of immu-
nity has been carried out such as C5a inhibitor used to
treat sepsis in mice [69], Fms-like tyrosine kinase 3 ligand
(Flt3L) used to stimulate the expansion and differentiation
of NK cells and dendritic cells (DC) in infectious mice, and
IFN γ used to restore energy metabolism in tolerant mono-
cytes of mice [70]. And in clinical, the administration of
GM-CSF therapy was showed to facilitate the reversal of
immunoparalysis in patients with multiple organ dysfunc-
tion syndrome (MODS) [71]. As SIMD is characteristic
with insufficient function without obvious necrosis of myo-
cardial cells, it will improve after sepsis is over. Therefore,
enhancing body immunity as mentioned examples including
enhancing the function of associated cytokines, complement,
immune cells and their energy metabolism will contribute
to SIMD directly and indirectly. As further explanation, for
the heart function under the condition of immunosuppres-
sion, clearing necrotic or apoptotic myocardial cells will
also further weaken the function of the innate immune cells
[72], which is not beneficial for the recovery [73]. The func-
tion of immune cells will be impaired and further apoptosis

Fig. 2  Body immune reaction

is activated by both patho-
gens and their metabolites via
PAMPs and DAMPs in sepsis.
Immunosuppression involving
innate and adaptive immunity
has always been seen in sepsis
including lymphocyte apoptosis.
Pyroptosis can also be activated
after detecting the LPS invasion
in cytosol. GPx4: glutathione
peroxidase 4; NF-kB: nuclear
factor kB; PRRs: pattern recog-
nition receptors

13
384
will be induced by the swallowed pathogen which cannot
be cleared, if the mitochondria are reduced to an extent via
mitophagy. Therefore, enhancing the function of immunity
and treating the primary infection can decrease the apopto-
sis of immune cells and the proportion of pyroptosis. It can
further improve the clearance of pathogens by host immune
cells and weaken the suppressing signal from the inflamma-
tory environment, further recovering myocardial cells after
the fading of related stimulus of sepsis.
Metabolism reprogramming is pivotal
in SIMD
In SIMD, metabolism reprogramming would occur in both
immune cells and myocardial cells. Under the homeostatic
condition, immune cells rely on oxidative phosphorylation
as the energy sources of ATP production. It will be shifted to
aerobic glycolysis during sepsis, which is known as Warburg
effect [3]. It was suggested that the glycolysis of macrophage
facilitated a macrophage proinflammatory phenotype and
induced IL-1β production [3, 74]. Moreover, aerobic glyco-
lysis could provide ATP for the immune response immedi-
ately [75]. Aerobic glycolysis exists during critical illness in
both immune cells and the other cells [76]. And if fission,
mitophagy, and aerobic glycolysis occur in myocardial cells,
it will reduce the damage from mtROS and keep myocar-
dial cells from massive apoptosis, which provide myocardial
cells more opportunities to recover after sepsis. However,
the inhibition of aerobic glycolysis by 2-DG significantly
improves the survival outcome in bacterial sepsis [77]. It
is because lactate significantly increases after the shift of
the energy metabolism to glycolysis during sepsis. And the
immunosuppressive effects of the tumor-derived lactate have
been shown on a variety of cell types in the surrounding
microenvironment [78], and lactate has been suggested to
induce M2-like macrophage polarization through an HIF-
1a-dependent mechanism [79]. According to the content
mentioned above, if the inhibition of aerobic glycolysis is
applied during immunosuppression, it has the similar role
with the enhancement of body immunity, as it can alleviate
the immunosuppressive effects of lactate by decreasing its
production.
Another question is whether SIMD is mainly caused
by inflammatory environment because of both slightly
reversible damage and the epigenetic regulation of gene
expression. It has been demonstrated that sirtuin 1 and sir-
tuin 6 can epigenetically shift substrate selection in septic
mouse or human monocytes from the glucose fueling of
the immune resistance to the fatty acid fueling of immune
tolerance [80], and mitochondrial sirtuin 3 expression
could be increased by sirtuin 1 to support mitochondrial
catabolic energetics and activate the antioxidant pathways
13
H. Yang, Z. Zhang
[81]. Physiologically, oxidative phosphorylation is the
first choice, as ATP is the basis for cells. Even under the
depression of various signal pathways mainly and primar-
ily caused by PAMPs and DAMPs, the epigenetic regulat-
ing gene expression can have a more positive effect on
a healthy cell than on a suppressed cell in sepsis, which
can try to generate more ATP. In contrast, the signal of
mitophagy may be the dominant regulating signal in a
suppressed cell, which may also process the apoptosis or
necrosis when the damage is caused by severe inflamma-
tion (Fig. 1).
Conclusions
SIMD, as a common complication in septic patients, is asso-
ciated with increased mortality. Changes in any part of CICR
and excitation–contraction coupling (ECC) influence the
heart function upon exposure to inflammatory environment
and damage from inflammatory mediators and cytokines
after the initiation of an immune reaction on pathogens.
Mitophagy may be the compressive choice of a myocardial
cell when facing sepsis, and is even chosen in the case of
death through necrosis or apoptosis or swallowing by mac-
rophages and degeneration. Sepsis is a result of uncontrolled
primary and secondary infections under the condition of
abnormal immunity. Immunosuppression has always been
observed in the case of sepsis, featured by a significant apop-
tosis of immune cells and a comparative increase in regula-
tory T cell and IL-10. Enhancing the body’s immunity may
be more efficient to prevent or improve SIMD and control
sepsis, besides the treatment of the primary infection. How-
ever, the research on the correlation between mitophagy and
expression of GPx4, the recognition of the transitional or
cut-off point of SIMD and immunosuppression to achieve
early prevention, and the selection of the biomarkers that can
be used to indicate the possibility of SIMD and immunosup-
pression need further research.
Authors’ contributions Hang Yang contributed to design and draft the
manuscript. And Zhaocai Zhang contributed to design and review the
manuscript.
Funding This study was funded by National Natural Science Founda-
tion of China (Nos. 81772110, 82072202).
Declarations
Conflict of interest Author Hang Yang declares that she has no conflict
of interest. Author Zhaocai Zhang declares that he has no conflict of
interest.
Sepsis‑induced myocardial dysfunction: the role of mitochondrial dysfunction 385

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participants or animals performed by any of the authors. meability transition pore: channel formation by F-ATP synthase,
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