Hydrogen sulfide and mitochondria
There are different opinions about the role of hydrogen sulfide (H2S) in catalytic and energy processes, but the biochemistry of all possible effects of H2S is not well studied yet. The enzymatic synthesis of H2S is catalyzed by cystathionine-γ-lyase, cystathionine-β-synthase, cysteine aminotransfer...
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Gerush, I.V. Ferenchuk, Ye.O. 2019-06-15T14:53:42Z 2019-06-15T14:53:42Z 2019 Hydrogen sulfide and mitochondria / I.V. Gerush, Ye.O. Ferenchuk // Вiopolymers and Cell. — 2019. — Т. 35, № 1. — С. 3-15. — Бібліогр.: 84 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000998 https://nasplib.isofts.kiev.ua/handle/123456789/154380 577.115+577.122:612.826.33.015.22:616.379-008.64 There are different opinions about the role of hydrogen sulfide (H2S) in catalytic and energy processes, but the biochemistry of all possible effects of H2S is not well studied yet. The enzymatic synthesis of H2S is catalyzed by cystathionine-γ-lyase, cystathionine-β-synthase, cysteine aminotransferase and in mitochondria by 3-mercaptopyruvate sulfurtransferase only. H2S may function as an energy substrate to sustain the ATP synthesis under stress conditions, but in high concentration H2S inhibits respiratory complex IV, blocking electron transport and proton pumping. The interaction between glucose in high concentrtaion, H2S, and the KATP channels may constitute a novel mechanism for the control of insulin secretion. The positive effect of H2S on the bioenergetic function of mitochondria may be used in therapy of many diseases. Існуть різні дані про роль гідроген судьфіду (H2S) в каталітичних та енергетичних процесах, але біохімічні механізми різноманітних ефектів H2S ще недостатньо вивчені. Ферментативний синтез H2S здійснюється цистатіонін-γ-ліазою, цистатіонін-β-синтазою, цистеїн амінотрансферазою, а в мітохондріях – 3-меркаптопіруват сульфуртрансферазою. H2S може функціонувати як енергетичний субстрат для підтримки синтезу АТФ в умовах стресу, але при високій концентрації молекула інгібує комплекс IV, блокуючи перенесення електронів. Взаємодія між високим рівнем глюкози, сірководнем і KATP-каналами може стати новим механізмом контролю секреції інсуліну, а ефект H2S на біоенергетичну функцію можна застосовувати при ускладненнях багатьох захворювань. Существуют различные данные о роли сероводорода (H2S) в каталитических и энергетических процессах организма, но биохимические механизмы всевозможных эффектов H2S еще недостаточно изучены. Ферментативный синтез H2S осуществляется цистатионин-γ-лиазой, цистатионин-β-синтазой, цистеин аминотрансферазой, а в митохондриях – 3-меркаптопируват сульфуртрансферазой. H2S может функционировать как энергетический субстрат для поддержания синтеза АТФ в условиях стресса, но в высокой концентрации молекула ингибирует комплекс IV, блокируя перенос электронов. Взаимодействие между высоким уровнем глюкозы, сероводородом и KATP-каналом может стать новым механизмом контроля секреции инсулина, а эффект H2S на биоэнергетическую функцию возможно применять при осложнениях многих заболеваний. en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell Reviews Hydrogen sulfide and mitochondria Гідроген сульфід і мітохондрія Сероводород и митохондрия Article published earlier |
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Hydrogen sulfide and mitochondria |
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Hydrogen sulfide and mitochondria Gerush, I.V. Ferenchuk, Ye.O. Reviews |
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Hydrogen sulfide and mitochondria |
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Hydrogen sulfide and mitochondria |
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Hydrogen sulfide and mitochondria |
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Hydrogen sulfide and mitochondria |
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hydrogen sulfide and mitochondria |
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Gerush, I.V. Ferenchuk, Ye.O. |
| author_facet |
Gerush, I.V. Ferenchuk, Ye.O. |
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Reviews |
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Reviews |
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2019 |
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Вiopolymers and Cell |
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Інститут молекулярної біології і генетики НАН України |
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Article |
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Гідроген сульфід і мітохондрія Сероводород и митохондрия |
| description |
There are different opinions about the role of hydrogen sulfide (H2S) in catalytic and energy processes, but the biochemistry of all possible effects of H2S is not well studied yet. The enzymatic synthesis of H2S is catalyzed by cystathionine-γ-lyase, cystathionine-β-synthase, cysteine aminotransferase and in mitochondria by 3-mercaptopyruvate sulfurtransferase only. H2S may function as an energy substrate to sustain the ATP synthesis under stress conditions, but in high concentration H2S inhibits respiratory complex IV, blocking electron transport and proton pumping. The interaction between glucose in high concentrtaion, H2S, and the KATP channels may constitute a novel mechanism for the control of insulin secretion. The positive effect of H2S on the bioenergetic function of mitochondria may be used in therapy of many diseases.
Існуть різні дані про роль гідроген судьфіду (H2S) в каталітичних та енергетичних процесах, але біохімічні механізми різноманітних ефектів H2S ще недостатньо вивчені. Ферментативний синтез H2S здійснюється цистатіонін-γ-ліазою, цистатіонін-β-синтазою, цистеїн амінотрансферазою, а в мітохондріях – 3-меркаптопіруват сульфуртрансферазою. H2S може функціонувати як енергетичний субстрат для підтримки синтезу АТФ в умовах стресу, але при високій концентрації молекула інгібує комплекс IV, блокуючи перенесення електронів. Взаємодія між високим рівнем глюкози, сірководнем і KATP-каналами може стати новим механізмом контролю секреції інсуліну, а ефект H2S на біоенергетичну функцію можна застосовувати при ускладненнях багатьох захворювань.
Существуют различные данные о роли сероводорода (H2S) в каталитических и энергетических процессах организма, но биохимические механизмы всевозможных эффектов H2S еще недостаточно изучены. Ферментативный синтез H2S осуществляется цистатионин-γ-лиазой, цистатионин-β-синтазой, цистеин аминотрансферазой, а в митохондриях – 3-меркаптопируват сульфуртрансферазой. H2S может функционировать как энергетический субстрат для поддержания синтеза АТФ в условиях стресса, но в высокой концентрации молекула ингибирует комплекс IV, блокируя перенос электронов. Взаимодействие между высоким уровнем глюкозы, сероводородом и KATP-каналом может стать новым механизмом контроля секреции инсулина, а эффект H2S на биоэнергетическую функцию возможно применять при осложнениях многих заболеваний.
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0233-7657 |
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https://nasplib.isofts.kiev.ua/handle/123456789/154380 |
| citation_txt |
Hydrogen sulfide and mitochondria / I.V. Gerush, Ye.O. Ferenchuk // Вiopolymers and Cell. — 2019. — Т. 35, № 1. — С. 3-15. — Бібліогр.: 84 назв. — англ. |
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3
I. V. Gerush, Ye. O. Ferenchuk
© 2019 I. V. Gerush et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Bio-
polymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited
Reviews ISSN 0233-7657
Biopolymers and Cell. 2019. Vol. 35. N 1. P 3–15
doi: http://dx.doi.org/10.7124/bc.000998
UDC 577.115+577.122:612.826.33.015.22:616.379-008.64
Hydrogen sulfide and mitochondria
I. V. Gerush, Ye. O. Ferenchuk
Higher State Educational Establishment of Ukraine «Bukovinian State Medical University»
2, Theatralna sq., Chernivtsi, Ukraine, 58002
yelena_f@ukr.net
There are different opinions about the role of hydrogen sulfide (H2S) in catalytic and energy
processes, but the biochemistry of all possible effects of H2S is not well studied yet. The en-
zymatic synthesis of H2S is catalyzed by cystathionine-γ-lyase, cystathionine-β-synthase,
cysteine aminotransferase and in mitochondria by 3-mercaptopyruvate sulfurtransferase only.
H2S may function as an energy substrate to sustain the ATP synthesis under stress conditions,
but in high concentration H2S inhibits respiratory complex IV, blocking electron transport and
proton pumping. The interaction between glucose in high concentrtaion, H2S, and the KATP
channels may constitute a novel mechanism for the control of insulin secretion. The positive
effect of H2S on the bioenergetic function of mitochondria may be used in therapy of many
diseases.
K e y w o r d s: hydrogen sulfide, mitochondria, bioenergetics.
Introduction
The knowledge of hydrogen sulfide (H2S) as
a potent signaling molecule greatly advanced
over the last years, though the biomolecule is
known from the very beginning of the life
evolution. H2S is the hydrogenated sulfur com-
pound with the lowest oxidation state (-2). The
description of gas dates back to the 15th cen-
tury when it was named “hepatic air” [1]. The
first chemical synthesis was performed by Carl
Wilhelm Scheele in 1777 by mixing metal
sulfides with acid, and in 1796 Claude Louis
Berthollet studied its chemical composition.
The compound is a flammable, colorless, wa-
ter-soluble gas denser than air [2].
There are different opinions about the role
of H2S in synthetic, catalytic and energy pro-
cesses. The ways of the molecule synthesis in
mammals were ascertained in the 1940s. In the
1990s, the data on the modulatory and signa-
ling effects of H2S first appeared. H2S repre-
sents an inorganic reducing substrate for oxida-
tive phosphorylation in mammals [3]. The
interest in studying H2S was triggered by its
potential importance for health. The attempt
to describe the pathways of formation, to de-
termine a biological role, to characterize and
mailto:yelena_f@ukr.net
4
I. V. Gerush, Ye. O. Ferenchuk
explain the physiological effects and to syn-
thesize donors of the biomolecule are promis-
ing for innovation of the effective pharmaco-
logical treatment. H2S has important effects
on mitochondria. The biomolecule influences
the mitochondrial electron transport chain. And
the reactions with metal centers and thiol oxi-
dation products are possible mechanisms of
these biological effects [4].
Key biochemical questions are the role of
H2S in the bioenergetic processes and its influ-
ence on the diabetes development and its com-
plications. In this review, we give a short over-
view of the biological role of H2S in mitochon-
dria, the regulation of cellular bioenergetics
and the influence on diabetes mellitus.
The enzymology of H2S formation
In mammals, the endogenous H2S is synthe-
sized from homocysteine and cysteine through
the enzymes of the transsulfuration pathway.
These enzymes are cystathionine-β-synthase
(CBS), cystathionine-γ-lyase (CSE), cysteine
aminotransferase (CAT) and 3-mercaptopyru-
vate sulfurtransferase (3-MST). CBS
(EC 4.2.1.22), CSE (EC 4.4.1.1) are cytosolic
enzymes only, whereas CAT (EC 2.6.1.3) and
3-MST (EC 2.8.1.2) can be present in both
cytosol and mitochondria [5]. These enzymes
utilize L-cysteine as a substrate that can be
taken up with the diet, extracted from endog-
enous proteins, or synthesized endogenously
via trans-sulfuration of serine by L-methionine
[6, 7].
3-MST is involved in cyanide detoxification
as an enzyme that transfers the sulfane sulfur
from substrate to cyanide ion, giving nontoxic
thiocyanate and pyruvate. Zink is the cofactor
of 3-MST. CAT, CBS, and CSE are pyridoxal
phosphate-dependent enzymes that take part
in the synthesis of cysteine from methionine
and serine. CBS and CSE can execute alterna-
tive reactions that yield H2S [5]. The enzyme
cystathionine-β-synthase catalyzes the replace-
ment of serine with homocysteine forming
cystathionine and water. If cysteine is used
instead of serine, the products formed are cys-
tathionine and H2S. CSE catalyzes the elimina-
tion of cystathionine to produce cysteine, a-
ketobutyrate and ammonia. Alternatively, CSE
can form H2S from both cysteine and, less
significantly, homocysteine [7, 8].
The rhodanese family enzyme 3-MST cata-
lyzes the formation of pyruvate and a persul-
fide from cysteine derived 3-mercaptopyru-
vate. In the availability of thiols, the persulfide
can extricate hydrogen sulfide, composing an
alternative source of the compound [9].
Since there is a tissue-specific expression
of these enzymes, their contribution to the
production of H2S is different. CBS and
3-MST are the main sources of H2S in the
nervous system, whereas CSE dominates in
cardiovascular tissues and liver [10–13]. One
of the major organs regulating endogenous
H2S generation through cystathionine-β-
synthase and cystathionine-γ-lyase is the kid-
ney [14]. And an alternative pathway for H2S
formation is the reduction of some sulfur-
containing compounds. For instance, cysteine
persulfide (a product of the reactions of disul-
fides and sulfenic acids with H2S) may be
synthesized from cystine in the presence of
CBS or CSE [15, 16]; thiosulfate and gluta-
thione can produce glutathione persulfide in
the presence of sulfurtransferases [17], and
cysteine desulfurases can form a protein-
bound persulfide from cysteine. All above
5
Hydrogen sulfide and mitochondria
persulfides can release H2S in the presence of
necessary reductants [18, 19].
The role of H2S in the respiratory
chain
The catabolic pathway of H2S in mitochondria
contains mitochondrial inner-membrane-bound
sulfide quinone reductase (SQR), which fixes
H2S to sulfite (SO3
2- ) to produce thiosulfate
(S2O3
2-); thiosulfate sulfurtransferase ((TST)
another name is rhodanese), reducing sulfite
from thiosulfate by fixating the sulfane sulfur
on an –SH-containing substrate, for example,
glutathione, to form a persulfide (R-S-SH)
species; mitochondrial matrix sulfur dioxygen-
ase, which oxidizes the sulfur atom extracted
from persulfide, converting it again into sulfite;
mitochondrial sulfite oxidase, which further
oxidizes sulfite into sulfate SO4
2-. H2S causes
protection from the oxidative stress in part by
the inner membrane component sulfide qui-
none oxidoreductase, the latter transferring the
electrons from H2S to the electron transport
chain and coenzyme Q [19-21].
The most effective system to control the
H2S levels appears to be localized in mitochon-
dria and is evolutionary related to the detoxi-
fication and energy producing systems. The
fact that the evident tissue formation of H2S
under aerobic conditions is much lower than
that under anaerobic conditions supports the
idea that the main consumption pathways of
H2S are oxygen-dependent. In mammalian
cells, H2S is the first inorganic reducing sub-
strate for oxidative phosphorylation [3].
The mitochondrial hydrogen sulfide oxida-
tion pathway includes several enzymes, and
the first is sulfidequinoneoxidoreductase (SQR)
localized in the inner mitochondrial mem-
brane. Here, the flavoprotein catalyzes the
transfer of electrons from hydrogen sulfide to
coenzyme Q producing an intermediate per-
sulfide species that can transfer the sulfane
sulfur to a suitable acceptor, possibly glutathi-
one [22, 23]. The sulfane sulfur formed at the
expense of SQR can be oxidized to sulfite by
sulfur dioxygenase [24] or transferred to sulfite
to form thiosulfate by the action of enzymes
of the rhodanese family [25].
The findings of Bucci M et al. [26] provide
an evidence that H2S acts as an endogenous
inhibitor of the phosphodiesterase activity.
So, H2S is able to increase mitochondrial
energy metabolism by inhibiting phosphodi-
esterase 2A leading to increased mitochon-
drial cAMP [4, 27].
The oxidation of hydrogen sulfide in mito-
chondria is vital in intestinal tissues, in which
H2S formation by the microbiota is counter-
acted by the protective strategies developed
by colonocytes. It has been suggested that in
these cell types the oxidation of H2S can com-
pete with that of organic substrates, and com-
plexes I and II can act in reverse, accepting
electrons from reduced coenzyme Q so as to
consume H2S even if cytochrome C oxidase
is inhibited [28–32].
H2S in high concentrations inhibits com-
plex IV, decreases the rate of electron transport
and proton pumping [4]. This opposite role as
inhibitor determines that the mitochondrial
oxygen consumption first increases at low H2S
concentrations, but then decreases as the con-
centration of H2S increases. The inhibition of
the respiratory chain by exposure to H2S is
associated with toxic effects [33]. It is well-
known that ATP contains high-energy phos-
phate bonds and is produced in mitochondria
6
I. V. Gerush, Ye. O. Ferenchuk
and the cytosol via glycolysis, substrate-level
phosphorylation, and oxidative phosphoryla-
tion. And energy is released by hydrolysis of
the phosphate bond. Many chemoautotrophic
and photoautotrophic bacteria and certain an-
imals use sulfide as an energy substrate [34].
In the work [35], the vasorelaxant effect of
H2S is shown in vivo and in vitro. The intra-
venous bolus injection of H2S transiently de-
creased blood pressure of rats. The modula-
tory influence of H2S on KATP channels the
authors explained by a direct interaction of
H2S and KATP channel proteins. So, hydrogen
sulfide may induce the reduction of disulfide
bonds of the KATP channel protein. In other
words, H2S may function as an energy sub-
strate to sustain ATP synthesis under stress
conditions, for example, in hypoxia, it may
help to produce more ATP [34].
For the first time, the authors showed that
NO appears to be a physiological modulator
of the endogenous production of H2S by in-
creasing the CSE expression and stimulating
CSE activity. CBS and CSE can translocate to
mitochondria under stress conditions, to stim-
ulate mitochondrial H2S and adenosine triphos-
phate production [36–38].
Hydrogen sulfide can radically decrease
metabolic demand, meaning that the metabo-
lism of H2S in mitochondria may serve as a
means for energy supplementation. The cys-
teine level inside mitochondria is 3 times
higher than in the cytosol. CSE translocation
is promoted by the growing level of intracel-
lular calcium levels via the calcium ionophore.
The translocation of CSE to mitochondria
metabolizes cysteine, produces H2S inside
mitochondria, and stimulates the energy pro-
duction [34, 36].
3-MST and its role in the bioenergetic
process
In mitochondria a source of H2S is mercapto-
pyruvate sulfurtransferase, expressed predom-
inantly in kidney cells, liver cells, cardiac cells,
proximal tubular epithelium, pericentral hepa-
tocytes, and neuroglial cells [9-13].
The crystal structure of MST reveals a mix-
ture of the product complex containing pyru-
vate and an active site of cysteine persulfide
(Cys248-SSH), and a nonproductive interme-
diate in which 3-MP is covalently linked via
a disulfide bond to an active site of cysteine
[19]. According to study [38], in the crystal
structure of 3-MST an Asp-His-Ser catalytic
triadis positioned to activate the nucleophilic
cysteine residue and participate in general
acid-base chemistry, whereas the kinetic anal-
ysis shows that thioredoxin is likely to be the
principal physiological persulfide acceptor for
mercaptopyruvate sulfurtransferase.
An additional enzymatic reaction that oc-
curs mainly in mitochondria is the conversion
of 3-mercaptopyruvate to H2S and pyruvate.
The reaction is catalyzed by 3-MST and needs
the activity of CAT, which also is known as
aspartate aminotransferase, converting cysteine
and -ketoglutarate to glutamate and 3-mercap-
topyruvate. α-cysteine that is not generated in
mammalian tissues but can be consumed by
food is converted by α-aminotransferase to
3-mercaptopyruvate, a substrate for 3-MST [9,
13, 19].
The role of 3-MST in the regulation of cel-
lular bioenergetics is realized in several ways
[4, 39]. 3-MP in low concentrations produces
H2S and stimulates the effect on bioenergetic
parameters, and this process is suppressed by
the silencing of 3-MST. A higher activity of
7
Hydrogen sulfide and mitochondria
3-MST inhibits the cellular bioenergetic an-
swer, and limiting of SQR suppresses both
basal and 3-MP mediated activation of bioen-
ergetic function as well as the L-cysteine-
mediated stimulation of mitochondrial oxygen
consumption. Cysteine and α-ketoglutarate
activate the mitochondrial electron transport,
and these effects are attenuated by the CAT
inhibitor aspartate. The 3-MP-derived, 3-MST-
mediated production of H2S donates electrons
into the mitochondrial electron transport chain
via SQR at the level of Complex II. The acti-
vating effect of enzyme on bioenergetics de-
creased with oxidative stress. Since 3-MP is
the substrate for 3-MST, mercaptic acids struc-
turally similar to 3-MP would inhibit the activ-
ity of MST. Incidentally, ketobutyrate, keto-
glutarate, and pyruvate were shown to be un-
competitive inhibitors of 3-MST with respect
to 3-MP [29, 40–42].
H2S is eliminated following the persulfide
transfer in these reactions:
MST-SH +3-MP → MST-S-SH + pyruvate
MST-S-SH + R-SH → MST-SH + R-S-SH
R-S-SH + RSH→ R-S-S-R + H2S
Inhibition of mitochondrial Complex
IV by H2S
Mitochondria is one of the major sources of
reactive oxygen species (ROS), that causes
serious damage to tissues, the aging process
and different diseases. Mitochondrial
Complex IV is the last enzyme of the electron
transport chain in the inner mitochondrial
membrane, and is an essential component of
aerobic cell respiration and energy generation.
As the final enzyme in the respiratory chain,
it receives an electron from each of four cyto-
chrome C molecules, and transfers them to one
oxygen molecule, converting the latter to two
molecules of water. The process contributes to
the generation of transmembrane proton and
it has been established that H2S in high con-
centrations, binds to Complex IV, thereby in-
hibiting the binding of oxygen [43, 44].
The H2S metabolism occurs in three path-
ways: oxidation, methylation, and reaction
with cytochrome C and other metalloproteins
or disulfide-containing proteins. The acute
toxicity of hydrogen sulfide at the molecular
level has been attributed to the inhibition of
cytochrome C oxidase [45]. In [4] the authors
used the combination of three effects for ex-
plaining the complex mode of inhibition: re-
duction of the cytochrome a3 center, followed
by a reaction with molecular O2; reduction of
other centers and ligating the ferrocytochrome
a3 hem group
However, at lower H2S concentrations, a
non-competitive type of inhibition has also
been supposed (Fig. 1). Once the binding of
oxygen to Complex IV is inhibited, the inner
mitochondrial membrane potential is dissi-
pated and aerobic ATP generation is blocked
[30, 46].
The blocking of Complex IV by sulfide
includes not only the inhibition of cytochrome
aa3 but also a ‘false substrate’ pathway in
which a cysteine radical or copper-cysteine
complex reacts directly with molecular oxy-
gen. Then the electrons from sulfide follow the
normal oxidative way to Complex III, cyto-
chrome C, and Complex IV and then to ato mic
oxygen to form water [4, 47].
When compared to other substrates of the
mitochondrial respiratory chain (NADH,
FADH2, succinate, L-alphaglycerophosphate),
the yield of sulfide in terms of electrons to be
8
I. V. Gerush, Ye. O. Ferenchuk
used by the respiratory chain is relatively low:
two molecules of sulfide are necessary to pro-
vide two electrons. It is expensive in terms of
oxygen: for the same electron transfer in the
respiratory Complexes III and IV, sulfide oxi-
dation needs three times more oxygen. And
when it takes place, the yield of energy per one
oxygen atom consumed is low in comparison
with NADH or FADH2 generated by oxidation
of carbon-containing substrates, so sulfide may
appear as a poor energy substrate. Therefore,
although the exact role of this process remains
to be elucidated, sulfide may serve as an ‘emer-
gency’ substrate, or as a substrate that bal-
ances and can complement the electron-donat-
ing effect of Krebs cycle-derived electron
donors [33, 48–50].
In mitochondria, H2S acts as a cytoprotec-
tive factor inhibiting the activity of cyto-
chrome oxidase following ischemia/reperfu-
sion, upregulating the level of superoxide
dismutase, and downregulating the levels of
ROS. Inhibition of cytochrome oxidase often
occurs in the absence of high H2S levels in
tissue [33, 48].
In the work [47], the authors suggest that
H2S poisons mitochondrial respiratory chain
by binding to iron of cytochrome C oxygenase,
but it also helps to reduce mitochondrial dam-
age and provides cytoprotection. H2S also acts
both as neuroprotector increasing the produc-
tion of glutathione [51] and as a modulator of
the CSE translocation to mitochondria and the
supply of the cell with ATP during hypoxia [34,
Fig. 1. Synthesis of hydrogen sulfide and its role in the mitochondrial respiratory chain
9
Hydrogen sulfide and mitochondria
36, 37]. Because mitochondria play a key role
in cell death pathways, H2S is involved in
regulating apoptosis [52, 53]. Downregulation
of the endogenous H2S/CSE pathway, induced
by high salt concentration, was involved in
mitochondrion-related human vascular endo-
thelial cell apoptosis leading to the leakage of
mitochondrial Cyt-C, which activated
Caspase-9 and Caspase-3 [51, 54–55]. Not only
the concentration of H2S directs different mi-
tochondrial outcomes, but it may be also im-
portant where H2S is produced inside the cell.
The role of H2S in diabetes mellitus
and other diseases
The biological roles of endogenous H2S are
multiple and rapidly expanding. Its regulatory
functions span the nervous system, the regula-
tion of cellular metabolism, the regulation of
immunological and inflammatory responses,
and various aspects of cardiovascular homeo-
stasis. The metabolic pathway of H2S and mi-
tochondria take part in different pathological
processes in the organism, like diabetes mel-
litus, diseases of heart, liver, and kidney [56–
62]. It was experimentally confirmed signifi-
cant effects of H2S production or H2S donors
in cardiovascular diseases, including heart fail-
ure, ischemic myocardium, atherosclerosis, and
hypertension [53, 58, 63–65]. The authors [46,
58] studied the influence of H2S levels on car-
diac mitochondrial content. They found that
restoring H2S levels with H2S-releasing pro-
drug, SG-1002, in the heart failure increased
cardiac mitochondrial content, improved mito-
chondrial respiration, and ATP production ef-
ficiency, and as a result improved cardiac func-
tion. The study [66] indicates the involvement
of H2S in modulation of changes in the perme-
ability of mitochondrial membranes, which
suggests that H2S plays an important role in the
development of cardiovascular diseases.
Others authors reported the changes in
methabolism of gasotransmitter and a similar
protective effect of H2S in ischemia reperfu-
sion injury of the kidney [28, 54]. In the review
[67] the cellular and molecular mechanisms of
protection by H2S in experimental models of
chronic kidney disease are discussed.
H2S regulates some proteins involved in
cellular oxidative stress, which could result in
a protective effect against aging. It inhibits the
mitochondrial ROS production and prevents
activation of the adaptor protein p66Shc [68–
71] and reduces the advanced glycation end
products toxicity by persulfidating its receptor
for advanced glycation end products [69].
Some studies of diabetic disease show that
increased extracellular glucose induces mito-
chondrial dysfunction in endothelial cells [34,
57–59, 70]. This causes the inhibition of cel-
lular bioenergetics through the dysfunction of
mitochondrial electron transport and the gen-
eration of ATP [68, 71–72].
In work [74], the authors studied an impor-
tant mechanism for the fine control of insulin
secretion from pancreatic β-cells. The study
demonstrated that an increase in extracellular
glucose concentration lowers the endogenous
H2S level. The possible mechanism of interac-
tion among glucose, H2S, and the KATP chan-
nels may constitute a novel mechanism for the
control of insulin secretion from pancreatic
β-cells in any pathophysiological conditions.
The KATP channels are sensitive to the chang-
es in intracellular ATP concentration. Elevation
of intracellular ATP level leads to closure of
the KATP channels in many metabolically active
10
I. V. Gerush, Ye. O. Ferenchuk
cells. In this way, the KATP channel is a cou-
pling factor to link metabolic activity and
membrane excitability. When circulating glu-
cose level elevates, the glucose influx into
pancreatic β-cells increases as well as the ATP
production. Consequential closure of the KATP
channels on plasma membrane depolarizes the
membrane and opens the voltage-dependent
calcium channels. The final eventuality of this
chain reaction increased the insulin release due
to elevated intracellular free calcium. In the
study it was determined that the endogenous
H2S production from INS-1E cells varies in
vivo conditions, which significantly affects the
insulin secretion from INS-1E cells. H2S stim-
ulates the KATP channels in INS-1E cells, in-
dependently of the activation of cytosolic sec-
ond messengers, which may underlie H2S-
inhibited insulin secretion from these cells.
There is a hypothesis [71] that H2S provides
physiological reducing and antioxidant intra-
cellular environment within the endothelial
cells, which helps to support normal mitochon-
drial functions. So, ROS from hyperglycemic
mitochondria directly reacts with and con-
sumes the intracellular H2S, which then in-
duces additional mitochondrial dysfunction,
possibly by oxidative modification of mito-
chondrial proteins. This positive feed-forward
cycle may then lead to a mitochondrial dys-
function where molecular oxygen is utilized
to produce ROS instead of ATP, and where
mitochondrial efficacy is diminished.
Noteworthy, some authors [4, 52, 38, 70–
77] reported that H2S exerts protective effects
against the development of diabetic complica-
tions, at least protecting the mitochondria. The
level of sulfide is decreased in diabetes, in part
due to an increase in consumption of sulfide
by ROS production, which causes the down-
regulation of H2S-producing enzyme in endo-
thelial cells, CSE. The results of the study [78]
evidence that the CSE-produced hydrogen
sulfide protects beta-cells from glucotoxicity
via regulation of expression of the thioredox-
in binding protein-2 levels and thus prevents
the development of type 2 diabetes.
H2S has a protective effect on endothelial
cell apoptosis induced by high glucose level
[52]. This effect was linked to the increased
superoxide dismutases activity and decreased
generation of reactive oxygen species and
level of thiobarbituric acid products, which
subsequently attenuated the high glucose im-
paired antioxidant activities. Genetic expres-
sion or pharmacological supplementation of
H2S-producing enzymes in hyperglycaemic
cells reduces the mitochondrial ROS formation
[38] and exerts the cytoprotective effect, in-
cluding normalization of mitochondrial bioen-
ergetics (recovery of oxidative phosphoryla-
tion, inhibition of glycolysis) [35, 58].
Additionally, sulfide protects against the
activation of pro-inflammatory signaling path-
ways in endothelial cells with hyperglycemia
(inflammatory cytokine production and NF-κB
activation) [79-81], against reduction in matrix
protein synthesis and remodeling [82–84].
However, a specific role of H2S in some dis-
eases remains to be investigated.
Conclusions
In mammals, the endogenous H2S is synthe-
sized from homocysteine and cysteine through
the enzymes of the transsulfuration pathway.
These enzymes are cystathionine-β-synthase,
cystathionine-γ-lyase, cysteine aminotransfer-
ase, and mercaptopyruvate sulfurtransferase.
11
Hydrogen sulfide and mitochondria
In mitochondria, H2S is produced by mercap-
topyruvate sulfurtransferase. H2S may function
as the source of electrons to sustain ATP syn-
thesis under stress conditions, but in high con-
centration H2S inhibits Complex IV, blocking
electron transport and proton pumping.
The interaction between glucose in high
concentration, H2S and the KATP channel may
constitute a novel mechanism for the control
of insulin secretion. The positive impact of H2S
on bioenergetic function in mitochondria may
have a therapeutic effect against diabetic com-
plications. The problems discussed and the
processes of synthesis and regulation of H2S
enzymes in mitochondria need further investi-
gation in this promising field of research.
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Гідроген сульфід і мітохондрія
І. В. Геруш, Є. О. Ференчук
Існуть різні дані про роль гідроген судьфіду (H2S) в
каталітичних та енергетичних процесах, але біохіміч-
ні механізми різноманітних ефектів H2S ще недостат-
ньо вивчені. Ферментативний синтез H2S здійснюєть-
ся цистатіонін-γ-ліазою, цистатіонін-β-синтазою, цис-
теїн амінотрансферазою, а в мітохондріях – 3-меркап-
топіруват сульфуртрансферазою. H2S може функціо-
нувати як енергетичний субстрат для підтримки
синтезу АТФ в умовах стресу, але при високій концен-
трації молекула інгібує комплекс IV, блокуючи пере-
несення електронів. Взаємодія між високим рівнем
глюкози, сірководнем і KATP-каналами може стати
новим механізмом контролю секреції інсуліну, а ефект
H2S на біоенергетичну функцію можна застосовувати
при ускладненнях багатьох захворювань.
К л юч ов і с л ов а: гідрогену сульфід, мітохондрії,
енергетичний обмін.
Сероводород и митохондрия
И. В. Геруш, Е. А. Ференчук
Существуют различные данные о роли сероводорода
(H2S) в каталитических и энергетических процессах
организма, но биохимические механизмы всевозмож-
ных эффектов H2S еще недостаточно изучены.
Ферментативный синтез H2S осуществляется циста-
тионин-γ-лиазой, цистатионин-β-синтазой, цистеин
аминотрансферазой, а в митохондриях – 3-меркапто-
пируват сульфуртрансферазой. H2S может функцио-
нировать как энергетический субстрат для поддержа-
ния синтеза АТФ в условиях стресса, но в высокой
концентрации молекула ингибирует комплекс IV, бло-
кируя перенос электронов. Взаимодействие между
высоким уровнем глюкозы, сероводородом и KATP-
каналом может стать новым механизмом контроля
секреции инсулина, а эффект H2S на биоэнергетиче-
скую функцию возможно применять при осложнениях
многих заболеваний.
К л юч е в ы е с л ов а: сероводород, митохондрия,
энергетический обмен.
Received 06.12.2017
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