gases in the mitochondria

7/29/2019 Gases in the Mitochondria

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Review

Gases in the mitochondria

Pamela B.L. Pun 1, Jia Lu 2, Enci M. Kan 3, Shabbir Moochhala *

Combat Care Laboratory, Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, #12-00, Singapore 117510, Singapore

a r t i c l e i n f o

Article history:

Received 3 July 2009

Received in revised form 3 November 2009Accepted 7 December 2009

Available online 22 December 2009

Keywords:

Nitric oxide

Carbon monoxide

Hydrogen sulphide

Gasomodulators

Mitochondria

a b s t r a c t

Gasomodulators nitric oxide, carbon monoxide and hydrogen sulphide are important physiological

mediators that have been implicated in disorders such as neurodegeneration and sepsis. Some of their

biological functions involve the mitochondria. In particular, their inhibition of cytochrome c oxidasehas received much attention as this can cause energy depletion and cytotoxicity. However, reports that

cellular energy production and cell survival are maintained even in the presence of gasomodulators are

not uncommon. In both cases, modulation of mitochondrial targets by the gasomodulators appears to be

an important event. We provide an overview of the effects of the gasomodulators on the mitochondria.

2009 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

1. Introduction

Gasomodulators, also known as gasotransmitters, have

emerged over the last decade as important physiological mediators

involved in various organs such as the nervous and cardiovascular

systems (Moore et al., 2003; Wu and Wang, 2005; Olson and Don-

ald, 2009). To qualify as gasomodulators, gases should: (a) be able

to diffuse through biological membranes, (b) be produced endoge-

nously andthis production should be regulated, (c) mediate biolog-

ical processes at physiological concentrations, and (d) have specific

biological targets (Wang, 2002). Other properties proposed to be

common to gasomodulators include short half-lives and their pro-

pensity to cause damage when present in excess (Kasparek et al.,

2007). Numerous gases such as ammonia, nitrous oxide and sul-

phur dioxide are speculated to be of physiological significance (Li

and Moore, 2007). However, only three gases have thus far been

definitively established as gasomodulators, namely nitric oxide

(NO), carbon monoxide (CO) and hydrogen sulphide (H2S) (Wang,

2002). The relevance of gasomodulators in biology has previously

been reviewed in terms of their involvements in different organs

systems and/or diseases (Wang et al., 2006; Fukuto and Collins,

2007; Kasparek et al., 2007; Li and Moore, 2007). Briefly, at physi-

ological concentrations, all three gases participate in cell signalling

and regulate tissue function. For instance, in the gastrointestinal

(GI) tract, NO, CO and H2S all act on the GI smooth muscle cells

and inhibit GI contraction (Kasparek et al., 2007). Similarly, in

the cardiovascular system, all three gases promote vasodilation

and angiogenesis, resulting in cardioprotection (Li et al., 2009).

Within the context of diseases, the gasomodulators have attracted

significant attention particularly in the field of sepsis in which the

gases are thought to exert protective effects by variously acting as

antioxidants, decreasing inflammation or even inducing suspended

animation (Baumgart et al., 2009).

Unfortunately, gasomodulators could be detrimental when

present in excess. NO, for instance, is neurotoxic at high concentra-

tions and is believed to contribute to the pathogenesis of neurode-

generative disorders such as Parkinsons disease and Alzheimers

disease (Molina et al., 1998; Calabrese et al., 2007). Likewise,

excessive CO could cause brain damage by binding to, and thus

excluding oxygen from, haemoglobin (Prockop and Chichkova,

2007). Supra-physiological levels of H2S, meanwhile, may partici-

pate in the pathogenesis of a variety of conditions including

inflammation, sepsis and stroke (Lowicka and Beltowski, 2007).

Interestingly, a common feature of many of these conditions is

the mitochondria (Beal, 2007; Exline and Crouser, 2008). It appears

plausible then that one mechanism by which gasomodulators exert

biological functions involves mitochondrial targets. The purpose of

this review, therefore, is to provide a brief but concise overview on

the effects of gasomodulators in the mitochondria. We discuss

1567-7249/$ - see front matter 2009 Elsevier B.V. and Mitochondria Research Society. All rights reserved.doi:10.1016/j.mito.2009.12.142

Abbreviations: ATA, atmospheres absolute; CBS, cystathionine-b-synthase; CO,

carbon monoxide; COX, cytochrome c oxidase; CSE, cystathionine-c-lyase; ETC,electron transport chain; GI, gastrointestinal; H2O2, hydrogen peroxide; H2S,

hydrogen sulphide; HBOT, hyperbaric oxygen therapy; HO, heme oxygenase;

MAO, monoamine oxidase; mPT, mitochondrial permeability transition; mtDNA,

Mitochondrial DNA; mtNOS, Mitochondrial nitric oxide synthase; NO, Nitric oxide;

ONOO-, Peroxynitrite; ROS, Reactive oxygen species ; SQR, Sulphide-quino-oxido-

reductase; UCP, Uncoupling protein.

* Corresponding author. Tel.: +65 6485 7201; fax: +65 6485 7226.

E-mail addresses: [email protected] (P.B.L. Pun), [email protected] (J.

Lu), [email protected] (E.M. Kan), [email protected] (S. Moochhala).1 Tel.: +65 6485 7217; fax: +65 6485 7226.2 Tel.: +65 6485 7204; fax: +65 6485 7226.3 Tel.: +65 6485 7212; fax: +65 6485 7226.

Mitochondrion 10 (2010) 8393

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http://dx.doi.org/10.1016/j.mito.2009.12.142mailto:[email protected]:[email protected]:[email protected]:[email protected]://www.sciencedirect.com/science/journal/15677249http://www.elsevier.com/locate/mitohttp://www.elsevier.com/locate/mitohttp://www.sciencedirect.com/science/journal/15677249mailto:[email protected]:[email protected]:[email protected]:[email protected]://dx.doi.org/10.1016/j.mito.2009.12.142


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these effects independent of any disease and organ system, for

which the reader is referred to other excellent reviews (Moore

et al., 2003; Wu and Wang, 2005; Wang et al., 2006; Fukuto and

Collins, 2007; Kasparek et al., 2007; Li and Moore, 2007; Olson

and Donald, 2009). Our review focuses on the three established

gasomodulators, NO, CO and H2S.

2. Nitric oxide

The discovery that the endothelium-derived relaxing factor is

NO in 1987 (Palmer et al., 1987) led to a burgeoning research field

investigating the biological significance of NO. In particular, the ef-

fect of NO on the mitochondria is one relevant research field to

reactive oxygen species biology. NO synthesis is catalysed by NO

synthase (NOS) of which the neuronal NOS (nNOS), endothelial

NOS (eNOS) and inducible NOS (iNOS) are the most well known

with other known spliced and post-translationally modified vari-

ants. However, the source of NO in the mitochondria is still debat-

able, with many citing the presence of a putative mitochondrial

NOS (mtNOS) as a possible source.

The first reports of mtNOS came in 1995 where Bates et al. dem-

onstrated the immunocytochemical localization of NOS in the rat

mitochondria. Progressively, several other groups also reported

NOS function in the mitochondria (Ghafourifar and Richter, 1997;

Giulivi et al., 1998). Typically, NOS isoforms are encoded by nuclear

DNA rather than mtDNA. It has thus been postulated that mtNOS

may simply be a variant of the more established NOS isoforms

(nNOS, eNOS, or iNOS) that is synthesized in and translocated from

the cytosol into the mitochondria (Finocchietto et al., 2009). Ini-

tially, eNOS was touted as the cytosolic candidate (Kobzik et al.,

1995), followed by iNOS (Elfering et al., 2002). However, recent

data has indicated strong evidence that a modified nNOS may be

the primary candidate for mtNOS. Kanai et al. (2001) reported that

nNOS knockout in mice abolished calcium-induced mitochondrial

release of NO. Further evidence showed that the mechanism via

which nNOS translocates into mitochondria is through the process-

ing of a PDZ domain from 157 kDa to 144 kDa (Carreras et al.,2008). The presence of iNOS in mitochondria could be due to a

pathologic condition as iNOS was shown to be present in mito-

chondria during endotoxemia brought about in experimental sep-

sis models (Lisdero et al., 2004; Lopez et al., 2006).

Interestingly, another novel family of putative NOS, Arabidopsis

thaliana NOS1 (AtNOS1) which does not shown any homology with

existing animal NOSs was found to be associated with NO produc-

tion (Guo et al., 2003). The mammalian homolog of AtNOS1, the

mouse mAtNOS1, has also been characterized and is found to be

localized to the inner mitochondrial membrane of mouse fibro-

blasts (Zemojtel et al., 2006). Although NO from AtNOS1 has been

reported to protect against oxidative damage in plants (Guo and

Crawford, 2005), the functions of mATNOS1 in mammalians re-

main unclear and research is still in the in vitro stage which maynot reflect accurately the effects in in vivo physiological conditions.

As the community continues to determine whether eNOS,

nNOS, iNOS or even whether mAtNOS1 makes up the genuine

mtNOS, the levels of mtNOS and consequently, NO production have

been reported to be modulated by hormones (Carreras et al., 2001),

development and aging (Riobo et al., 2002; Valdez et al., 2004) as

well as environmental changes (Peralta et al., 1993). The effects

of different NO levels on mitochondria function especially in rela-

tion to its inhibition of cytochrome c oxidase (COX) will be dis-

cussed in the following paragraphs.

NO is an inhibitor of the electron transport chain (ETC), with the

propensity to affect the activities of possibly all complexes of the

respiratory chain. Most attention has focused on its influence on

COX activity. COX is the final complex in the ETC and mediatesthe reduction of oxygen to water. This complex contains a heme

a3CuB binuclear centre to which oxygen binds when both metals

are in the reduced state (i.e. Fe2+ and Cu+) (Tsukihara et al., 1996).

However, NO can compete with oxygen for binding to the same

site, resulting in competitive but reversible inhibition of COX

(Brown and Cooper, 1994; Cleeter et al., 1994). It has been sug-

gested that NO is not a typical competitive inhibitor which func-

tions simply by binding reversibly to COX (Pearce et al., 2003).

This stems from observations that the inhibitory effects on COX

of NO and cyanide (another COX inhibitor) are not additive (Pearce

et al., 2003). The authors of that study proposed that NO first binds

to the heme a3 site of COX. In the meantime, superoxide is formed

at the CuB site when Cu+ donates an electron to oxygen. The result-

ing superoxide reacts with NO to form peroxynitrite (ONOO). The

subsequent reduction of ONOO by COX then generates nitrite and

water. Should this hypothesis be true, one may expect that the for-

mation of ONOO at the binuclear centre of COX should render the

enzyme highly vulnerable to nitrosative damage. However, the

group has indicated the conversion of ONOO to nitrite and water

to be quick and facile, suggesting that ONOO will be so rapidly

converted to nitrite that it will not react with COX to cause dam-

age. Furthermore, studies by another group have found ONOO

to have little effect on COX activity in isolated rat heart mitochon-

dria (Radi et al., 1994; Cassina and Radi, 1996). However, the pro-

pensity of ONOO to inhibit COX appears to be dependent both on

cell type and ONOO concentration (Bolanos et al., 1995). Nonethe-

less, it remains plausible that even if ONOO is not quickly reacted

away, that it is unlikely to cause severe irreversible damage to the

COX protein.

NO could also participate in uncompetitive inhibition by bind-

ing to the oxidized form of the enzyme, forming nitrite in the pro-

cess and decreasing COX activity (Cooper et al., 1997). These two

modes of inhibition can be distinguished based on their sensitivity

to oxygen and light, with competitive inhibition being responsive

and uncompetitive inhibition being resistant to changes in either

parameter (Sarti et al., 2000; Mason et al., 2006). It is also apparent

from these unique characteristics that the two forms of inhibition

dominate under different conditions, with competitive inhibitionlikely to predominate when oxygen levels are low and COX is, for

the most part, in the reduced state. Conversely, uncompetitive

inhibition is more likely to occur under the opposite conditions

(Sarti et al., 2000; Mason et al., 2006). While oxygen can modulate

the inhibitory effects of NO by competing with it for binding to

COX, its effects on this process are likely to be manifold as oxygen

can influence NO synthesis and breakdown, thus regulating levels

of NO and its downstream activities, a prospect that has been pre-

viously discussed (Cooper and Giulivi, 2007). Fig. 1 summarizes the

inhibition of COX by NO under low and high oxygen conditions.

Based upon studies in isolated mitochondria, the IC50 of NO has

been determined to increase in direct proportion to the square of

the oxygen tension (Kovisto et al., 1997). As the typical oxygen

concentration in mammalian tissues is 30lM, it appears thatphysiological levels of NO (1200 nM) are sufficient to significantly

inhibit respiration (Brown, 1999) and be of cellular relevance.

Besides COX, NO and its derivative, ONOO, could also inhibit

the other complexes in the ETC (Bolanos et al., 1996; Cassina and

Radi, 1996; Lizasoain et al., 1996; Stadler et al., 1991a,b). The pre-

cise pathway by which such inhibition is achieved remains poorly

defined although there are candidate mechanisms including tyro-

sine nitration, S-nitrosation and damage to the ironsulphur (Fe

S) clusters of the complex (Brown, 1999; Brown and Borutaite,

2004; Welter et al., 1996). In addition, ONOO can decrease acon-

itase activity (Castro et al., 1994), thus reducing the availability of

substrates required for oxidative phosphorylation.

Since NO reduces electron flux through the respiratory chain, it

follows then that NO must increase reactive oxygen species (ROS)production by the ETC, and indeed, evidence for this is plentiful.

84 P.B.L. Pun et al./ Mitochondrion 10 (2010) 8393


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For instance, superoxide and hydrogen peroxide (H2O2) levels are

elevated in cells exposed to NO (Ponderoso et al., 1996; Wei

et al., 2000; Sarkela et al., 2001). NO and superoxide can further re-

act to formONOO, while hydrogen peroxide may go onto form the

highly reactive and damaging hydroxyl radical.

This formation of a cascade of reactive species could be detri-

mental and promote cell death by causing oxidative/nitrosative

damage to cellular components (Therond, 2006). For instance, per-

oxidative damage of cardiolipin disrupts the cardiolipincyto-

chrome c complex, leading to the release of cytochrome c

(Ushmorov et al., 1999; Vlasova et al., 2006). Similarly, oxidation

of protein thiols in the mitochondrial permeability transition

(mPT) pore leads to pore opening, consequently causing a drop in

mitochondrial membrane potential, mitochondrial swelling andfurther release of cytochrome c (Hortelano et al., 1997; Bal-Price

and Brown, 2000; Saviani et al., 2002). Additionally, ROS can acti-

vate signalling pathways such as that involving p38 MAPK, leading

to the up-regulation and translocation of pro-apoptotic proteins

like Bax to the mitochondria (Ghatan et al., 2000; Cheng et al.,

2001). It should be noted, however, that the ability of NO to induce

apoptosis is concentration-dependent, and that NO at low concen-

trations is anti-apoptotic rather than pro-apoptotic (Choi et al.,

2002; Yoshioka et al., 2006). However, when present in greater

abundance, and if ATP is available, NO can cause apoptosis by

the pathways mentioned above.

Given that NO inhibits respiration, ATP levels can be expected to

drop as a result. However, cells may be more resilient to NO-in-

duced declines in energy production and even apoptosis thanwould be expected in theory. The two main reasons for such resis-

tance lie in increased mitochondrial biogenesis and up-regulation

of glycolysis and glucose uptake. Firstly, NO, by activating guany-

late cyclase and increasing cGMP levels, activates mitochondrial

biogenesis in a PFC-1a and Tfam-dependent manner (Nisoli et al.,2003; Clementi and Nisoli, 2005). With more mitochondria, the en-

ergy production capacity of the cell, or tissue as a whole, is in-

creased, thus providing a buffer against any drop in ATP

production due to ETC inhibition predicted per mitochondrion.

Secondly, while high levels of ROS can be detrimental, more mod-

erate levels are important in cell signalling. In this context, ROS

generated by NO-mediated inhibition of the respiratory complexes

can participate in signalling pathways such as those involving Nrf2

and AMPK, leading to cytoprotection. For instance, Nrf2 activationinduces the expression of antioxidant genes, thus protecting

against oxidative damage and consequently apoptosis (Dhakshina-

moorthy and Porter, 2004). The NO-derived ONOO may also exert

an indirect antioxidant effect via the pentose phosphate shunt

which generates NADPH, a substrate crucial for the regeneration

of the antioxidant, glutathione (Garcia-Nogales et al., 2003). Acti-

vation of AMPK also protects cells by up-regulating glycolysis

and glucose uptake (Cidad et al., 2004; Almeida et al., 2005) to

compensate for any drop in ATP production due to respiratory inhi-

bition. Because ATP production via glycolysis is far less efficient

than that by oxidative phosphorylation (in terms of number of

ATP molecules produced per glucose molecule utilized), the ade-

quacy of such compensation is questionable. Nonetheless, the

maintenance of ATP production further protects the cell from

apoptosis as it makes possible the preservation of the mitochon-

drial membrane potential by allowing the reversal of the F0F1-ATP-

ase (Almeida et al., 2001). Taken together, these events minimize

oxidative damage, allow for a compensatory increase in ATP pro-

duction, and reduce the likelihood of apoptosis occurring, thereby

protecting the cell. Because they may occur to varying extents in

different cell types, some cells such as neuronal cells may be more

susceptible to NO toxicity relative to others like the glial cells

(Almeida et al., 2001; Bolanos and Almeida, 2006). As a result, cell

types with less capacity for glycolytic ATP production are more

likely to undergo necrosis than those with greater propensity for

glycolysis (Borutaite and Brown, 2003).

Considering the above points, it is apparent that NO could be

detrimental or protective to the cell, depending on factors such

as cell type and NO levels. To maintain such a delicate balance in

NO levels requires a homeostatic pathway governing NO levels

within mitochondria. One such candidate pathway involves mito-

chondrial nitric oxide synthase (mtNOS; a proposed NOS isoform

that exists in the mitochondria in close association with COX of

the ETC) (Ghafourifar and Richter, 1997; Persichini et al., 2005)

and mitochondrial calcium concentration ([Ca2+]m). High [Ca2+]m

increases mtNOS activity, generating more NO within the mito-

chondria. NO, in turn, opens the mPT pore, decreasing mitochon-

drial membrane potential. As a result, Ca2+ is released from themitochondria. NO also reduces Ca2+ uptake into the mitochondria,

further decreasing [Ca2+]m. As [Ca2+]m drops, mtNOS activity corre-

spondingly decreases. NO levels thus decrease and [Ca2+]m subse-

quently increases, repeating the cycle again (Ghafourifar and

Richter, 1999).

3. Carbon monoxide

CO is produced endogenously as a by-product of heme break-

down in a process catalysed by heme oxygenase (HO)-1 and 2

(Yoshida and Kikuchi, 1974). Although heme catabolism by HO also

generates biliverdin and free iron, each of which has its own phys-

iological roles (Elbirt and Bonkovsky, 1999; Foresti et al., 2004), the

effects of HO-1 on the mitochondria appears to be due predomi-nantly to CO production (DAmico et al., 2006).

In the mitochondria, CO has been shown to inhibit COX ( Peter-

sen, 1977; Pankow and Ponsold, 1984; Miro et al., 1998; Alonso

et al., 2003; Iheagwara et al., 2007; Zuckerbraun et al., 2007). Like

NO, CO achieves this inhibitory effect by competing with oxygen

for binding to the reduced form of the enzyme. Unlike NO, this is

the only mode of inhibition inhibition of COX by CO. That is, CO

is unable to bind to the oxidized form of COX and therefore, its

inhibition is exclusively competitive (Petersen, 1977). CO itself is

converted to carbon dioxide by COX after binding (Young and

Caughey, 1986). It is thought that under physiological conditions,

CO-mediated inhibition of COX is unlikely to be significant because

CO concentration is probably very low due to its relatively high

affinity for haemoglobin and myoglobin, meaning that any avail-able CO is far more likely to bind to these proteins than to COX

COX

CuAI

heme aII

CuBI

heme a3II

Low Oxygen

Low

[NO]

NO

O2

O2

.-

B. ROSproduction

ONOO-

2H+

H2O

+

NO2-

fast

C. Rapid conversionterminates NO inhibitive effects

H2O

2

.-

High[NO]

4e-

A. CompetitiveInhibition

Fig. 1. Summary of effects of NO inhibition on COX during low oxygen condition.

(A) NO competes with O2 and binds reversibly to COX, leaving O2 to be reduced by

COX to superoxide (O2 ). (B) ROS production is propagated as superoxide is either

converted to H2O2 (at low [NO]) or peroxynitrite (at high [NO]). (C) Rapid

conversion of peroxynitrite to H2O and NO3 terminates by-product effects of NO

inhibition on COX.

P.B.L. Pun et al./ Mitochondrion 10 (2010) 8393 85


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(Cooper and Brown, 2008). However, the veracity of this statement

remains to be confirmed. Afterall, it appears that a mitochondrial

isoform of HO-1 exists (Converso et al., 2006; Slebos et al., 2007).

If this was true, the local concentration of CO at the site of COX

within the mitochondria could be sufficiently high for significant

inhibition of COX by CO. In addition, interactions between CO

and NO (as will be discussed later in this review) could modulate

the influence of CO on COX as well.

Even if endogenous CO production is indeed too low to produce

significant COX inhibition, the pathological relevance of such inhi-

bition cannot be ignored especially since exogenous CO from con-

ditions such as smoke exposure during fires can greatly elevate CO

levels within the body (Varon et al., 1999; Alarie, 2002). Therefore,

in such situations, the CO concentration in blood and tissues could

increase so much as to cause significant inhibition in vivo.

COX inhibition by CO (Fig. 2) causes electrons to accumulate

within the ETC, resulting in increased ROS generation by the mito-

chondria. A study by Zuckerbraun et al. (2007) found that treat-

ment of cells with CO generated higher levels of ROS than similar

treatment with antimycin A alone. Application of both CO and anti-

mycin A together led to ROS production that was increased relative

to baseline (non-treated cells) but which was comparable to that

generated by antimycin A treatment alone and significantly less

than that due to CO by itself. The authors of that study thus con-

cluded that the site of CO-induced ROS generation was complex

III. The amount of ROS generated is dependent on the concentra-

tion of CO. The exposure of cultured cells to low levels of exoge-

nous CO (


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els is consistent with studies from Kristal et al. (1997), and Craw-

ford et al. (1997) investigating ROS-mediated inhibition of mRNA

transcription and increased degradation respectively. Although

no direct cause-effect relationship has been demonstrated be-

tween CO and transcription of COX1, there does appear to be a po-

tential for such a causative relationship to exist.

Given that CO inhibits COX of the ETC, it is reasonable to predict

that ATP levels should consequently decrease. In addition, CO

exposure causes mitochondrial membrane hyperpolarisation. As

this can be prevented by oligomycin (an inhibitor of the F0F1-ATP-

ase), it appears that this hyperpolarisation is due to reversal of the

F0F1-ATPase (Zuckerbraun et al., 2007). That is, protons are ex-

truded at the expense of ATP hydrolysis. Yet despite this, several

studies have found ATP levels to be maintained or even increased

by CO treatment (Piantadosi et al., 1988; Brown and Piantadosi,

1992; Matsuoka et al., 1993; Lavitrano et al., 2004; Tsui et al.,

2005; Zuckerbraun et al., 2007). Even where a drop in ATP levels

was reported, the decrease appeared to be short-term (Sokal

et al., 1982). Prolonged CO exposure led instead to an elevation

of ATP content of tissues (Sokal et al., 1982). These findings suggest

that CO exposure conditions cells such that compensatory re-

sponses are invoked which maintain ATP levels.

Similarly, despite CO increasing ROS production and thus caus-

ing oxidative damage (Piantadosi et al., 2006; Taskiran et al., 2007;

Kim et al., 2008; Scragg et al., 2008; Lancel et al., 2009), cells that

had received prior treatment with CO are generally more resistant

to subsequent oxidative stress and are less likely to undergo apop-

tosis as a result (Kim et al., 2006; Li et al., 2006). Besides, while CO

induces mPT in the short-term after initial exposure, there is recov-

ery by day 7 even in the continued presence of CO(Piantadosi et al.,

2006). Again, these observations support the idea of a CO-inducible

pre-conditioning of cells.

In both situations, the pre-conditioning appears to be ROS-med-

iated. The rapid elevation of ROS levels induced by CO leads to the

expression of antioxidants such as MnSOD (Frankel et al., 2000;

Thom et al., 2000; Liu et al., 2006; Piantadosi et al., 2008). This en-

zyme catalyses the dismutation of superoxide to H2O2, therebyincreasing the mitochondrial H2O2 leak .Among others, mitochon-

drial H2O2 can then activate PKB. PKB in turn deactivates GSK3b.

This process releases Nrf2 which binds the ARE within the nucleus

and induces Nrf1 expression (Piantadosi et al., 2008). Both Nrf1

and Nrf2 subsequently trigger mitochondrial biogenesis in a

PGC1a-Tfam-dependent pathway. In fact, as low as picomolar lev-els of CO can induce mitochondrial biogenesis. Although CO could

also activate PGC1a via guanylate cyclase, this is unlikely to be animportant means in cells as CO has far lower affinity for guanylate

cyclase than NO (Suliman et al., 2007). CO can further exert anti-

inflammatory and anti-apoptotic effects via molecules such as

PPARc (Bilban et al., 2006), NFjB (Brouard et al., 2002; Kimet al., 2006), STAT (Zhang et al., 2005) and p38MAPK (Silva et al.,

2006; Kohmoto et al., 2007). The precise mechanism by whichCO regulates these molecules has yet to be defined. It has, however,

been suggested that there exist transcription factors that are regu-

lated by gases such as CO although it remained to be seen which

signalling pathways are activated downstream of these genes

(Bilban et al., 2008). CO could further protect against apoptosis

by binding to cytochrome c of the cytochrome ccardiolipin com-

plex, thus inhibiting its peroxidise activity and preventing cell

death (Kapetanaki et al., 2009). The activation of these manifold

pathways collectively have the following effects: (i) The induction

of antioxidants in response to the initial rise in ROS production and

ARE binding by Nrf2 conditions cells to be more resistant to oxida-

tive stress; (ii) Mitochondrial biogenesis can be expected to help

compensate for any decrease in ATP production by each mitochon-

drion. (iii) The expression of genes like TGFb downstream of themajor transcription factors e.g. NFjB, together with the mainte-

nance of cytochrome ccardiolipin integrity, inhibits apoptosis

and inflammation. One should note, however, that at very high lev-

els of CO, excessive ROS production may overwhelm even these

compensatory mechanisms and cause severe cell damage, leading

to cell death either by apoptosis (Piantadosi et al., 1997; Uemura

et al., 2001; Tofighi et al., 2006) or necrosis (Wang et al., 1990;

Piantadosi et al., 1997; Uemura et al., 2001).

4. Hydrogen sulphide

H2S is produced from L-cysteine in a process catalysed by the

enzymes cystathionine-c-lyase (CSE) and cystathionine-b-syn-thase (CBS) (Stipanuk and Beck, 1982). Although the mitochondria

are a rich source of acid-labile sulphur, it is unlikely to be a major

source of sulphide in cells as the mitochondrial pH is not usually

acidic. Rather it appears that under physiological conditions, intra-

cellular H2S largely originates from bound sulphur released upon

alkalinisation of the cytoplasm e.g. during neuronal excitation

(Ishigami et al., 2009). While this contradicts earlier findings that

as much as a quarter of endogenous sulphide in rat brains is found

in the mitochondria (Warenycia et al., 1989), it should be noted

that experimental conditions differed between the two studies,

with the earlier one having been conducted at acidic pH and the

more recent study at alkaline pH. Besides, even assuming the mito-

chondria to contain most of a cells sulphur content, it does not

necessarily mean that the mitochondria is the main source of

endogenous and active sulphide because that would require the

sulphide to be released from its stores and near-neutral pH condi-

tions within the mitochondria makes this unlikely.

Like NO and CO, H2S is known to affect the activity of the respi-

ratory chain. To be more specific, H2S is both a substrate and inhib-

itor of the ETC (Nicholls and Kim, 1982). At low concentrations

(


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dase) prevents their accumulation in the ETC and, hence, reduces

ROS generation. In addition, it is possible that the reversal of reac-

tions at complex II prevents the build-up of substrates intended for

oxidative phosphorylation, thereby allowing the substrates to be

similarly channelled elsewhere e.g. to glycolysis. It has been sug-

gested, however, that since ATP generation by glycolysis is far less

productive than that by oxidative phosphorylation, that there is

still likely to be a shortfall in ATP production (Leschelle et al.,

2005).

Indeed, ATP levels have been found to decrease at high H2S con-

centrations (Nicholson et al., 1998; Eghbal et al., 2004; Hildebrandt

and Grieshaber, 2008), indicating that the demand for ATP out-

strips supply. Besides simple inhibition of COX enzyme activity,

H2S can further decrease ATP production by up-regulating uncou-

pling protein (UCP)-2 and down-regulating the protein expressions

of subunits I and II of COX (Leschelle et al., 2005). The authors sug-

gested these events to be part of an adaptation process to H2S. For

example, increasing UCP-2 expression, though decreasing ATP pro-

duction, also reduces ROS generation by the ETC, thus protecting

the cell from oxidative stress. The reduction in expression of the

COX subunits, on the other hand, may be a means to conserve met-

abolic expenses. This argument was based on the belief that at high

H2S concentrations, COX would be inhibited anyhow. Thus it

would be of little use to synthesize more COX. Down-regulating

COX expression would therefore minimize wastage of and allow

resources to be put to better use. Fig. 3 summarizes the inhibition

of COX by H2S under high oxygen conditions.

Other evidence that cells appear to be able to adapt to H2S and/

or undergo pre-conditioning in its presence is also available. For in-

stance, in lung mitochondria from H2S-treated rats, COX activity

decreased initially, then recovered to baseline by 24 h post-expo-

sure (Khan et al., 1990). Similarly, while single acute exposure to

H2S significantly inhibits COX activity in rat nasal respiratory epi-

thelium, prolonged exposure produced no apparent change. This

lack of effect was concomitant to a regeneration of the nasal respi-

ratory mucosa, suggesting that the regenerated mucosa is condi-

tioned to withstand the effects of H2S (Dorman et al., 2002).Furthermore, H2S increases lactate release without any effect on

its oxidation, pointing towards an up-regulation of glycolysis

which may compensate for any declines in ATP production due

to COX inhibition (Leschelle et al., 2005). Such compensation,

unfortunately, is unlikely to be sufficient as has been mentioned

above. In addition, cells pre-treated with H2S are more resistant

to oxidative stress, likely because of an increase in GSH synthesis

triggered by elevated ROS levels (Kimura and Kimura, 2004;

Kimura et al., 2006). These observations collectively indicate a

compensatory response to H2S, which would suggest that cells

should have greater resilience to subsequent H2S treatment.

However, this may not always hold true as one study has re-

ported that pre-treated cells are actually more vulnerable than

cells without prior H2

S exposure to COX inhibition by a second

low doseof H2S (Leschelle et al., 2005). The authors attributed their

observations to the presence of an excess capacity for oxidative

phosphorylation in non-pre-treated cells which was lost during

the first exposure period in pre-treated cells in which COX expres-

sion was found to be down-regulated. Alternatively, it is also pos-

sible that vulnerability to H2S may be cell-specific. Afterall, while

lung cells appear to be susceptible to H2S-mediated COX inhibition,

liver cells seem more resistant, with no COX inhibition recorded

even at levels as high as 400 ppm H2S (Dorman et al., 2002). The

reason for such disparities is unclear, although it may likewise be

due to differences in buffering capacity against COX inhibition. A

third possibility is that the model system in which the effects of

H2S are investigated could itself influence outcome. For example,

while the above study, which was conducted in rats, found the li-

ver to be resistant to H2S-induced COX inhibition (Dorman et al.,

2002), a separate study using isolated rat hepatocytes in culture re-

ported a significant decrease in COX activity following H2S expo-

sure (Eghbal et al., 2004). Again, there is no proven explanation

as yet for such discordance. We speculate that the compensatory

responses invoked in whole animals may involve multiple organ

systems and, therefore, differ from that seen in isolated systems

such as cell cultures, resulting in varying extents of protection

against the negative effects of H2S.

Not surprisingly then, depending on the study model and the

concentration of H2S used, ROS levels may or may not be signifi-

cantly altered by H2S treatment. Increased ROS production can lead

to apoptosis by inducing mPT (Eghbal et al., 2004). H2S exposure

further promotes apoptosis by inducing cytochrome c release from

the mitochondria, triggering Bax translocation to the mitochon-dria, stabilizing pro-apoptotic molecules like p21 and down-regu-

lating anti-apoptotic proteins like Bcl-2 (Baskar et al., 2007;

Adhikari and Bhatia, 2008).

However, despite appearing to be pro-apoptotic, a recent study

reported the contrary with H2S mitigating rotenone-induced apop-

tosis in neuroblastoma cells (Hu et al., 2009).In that study,H2S was

found to, among other things, prevent rotenone-induced mito-

chondrial membrane depolarization, cytochrome c release and de-

crease in Bcl-2:Bax ratio. Intriguingly, H2S itself is known to cause

loss of mitochondrial membrane potential, cytochrome c release

and dampening of the Bcl-2:Bax ratio (Eghbal et al., 2004; Baskar

et al., 2007; Adhikari and Bhatia, 2008). The authors suggested that

H2S attenuated rotenone-induced apoptosis by inhibiting the acti-

vation of the pro-apoptotic MAPK pathway in a process mediatedby mitochondrial ATP-sensitive potassium (mitoKATP) channels

(Hu et al., 2009). This stemmed from observations that blockage

of these channels prevented H2S-mediated protection. That H2S

activation of the mitoKATP channels is cytoprotective has also been

suggested in a separate study on cortical neuronal cell cultures

(Kimura et al., 2006). We suggest that H2S further affords protec-

tion against rotenone by increasing glutathione biosynthesis, thus

improving the antioxidant to oxidant status of cells. However, it

should be noted that no measures of glutathione was done in the

study involving rotenone and our suggestion remains purely

speculative.

Even assuming these explanations to be wholly accurate, it re-

mains difficult to reconcile the apparently dual and opposite ef-

fects of H2S on apoptosis for the following reasons: for ROS toinduce apoptosis, ROS levels must be so high as to cause significant

Electrons from

sulphide oxidation

High Oxygen

COX

CuAII

heme aIII

CuBII

heme a3III

A. Non-CompetitiveInhibition of COX

inhibits ETC at complex IV

H2S

C. Modulate COXexpression

e-

e-

e-

e-

H2S

Decreased

expression of

COX subunits

O2

H+

Complex II

B. Reversal of catalyticreactions at Complex II

Fumarate

Succinate

Fig. 3. Summary of effects of H2S inhibition on COX at high oxygen condition. (A)

H2S binds non-competitively to COX. (B) Electrons from sulphide oxidation are

channelled through complex II, causing a reversal of its catalytic reaction (i.e.

producing succinate from fumarate) when H2S concentrations are high. (C) H2Sdown-regulates expression of COX subunits.



7/11

cell damage. The effects of H2S on ROS production are dose-depen-

dent (Eghbal et al., 2004). Therefore, H2S levels must be sufficiently

high to be pro-apoptotic. However, a similar argument is valid

when considering the anti-apoptotic effects of H2S. It appears that

such cytoprotection is dependent on the opening of the mitoKATPchannel. For these channels to open, ATP levels must drop signifi-

cantly. This too only occurs at high H2S concentration. Based on

these arguments, both detrimental and protective effects would

take place in situations where H2S levels are high. However, either

one or the other has to dominate in the outcome, and what influ-

ences the balance between the two processes has yet to be defined.

It is possible that there is a threshold level of H2S below which the

anti-apoptotic events dominate, and above which cell death oc-

curs. However, no study is known to us that has clearly demon-

strated and defined the existence of such a threshold and further

investigation is required to determine the veracity of our

hypothesis.

5. Interactions between the gasomodulators

It is apparent from available literature that NO, CO and H2S

share several similarities (Fig. 4). To put it very generally, all three:

1. are gasomodulators,

2. can inhibit COX and, in the broader perspective, reduce oxida-

tive phosphorylation,

3. have the potential to increase ROS production, induce apoptosis

and cause mitochondrial dysfunction,

4. yet, at the same time, also induce compensatory responses such

as increased mitochondrial biogenesis, possibly via signalling

pathways involving, for example, Nrf2 and various kinases,

5. in fact, at low gas concentrations, these events may even be

cytoprotective.

Given such similarities, NO, CO and H2S are naturally expected

to interact with and modulate each other. There are multiple

pieces of evidence supporting this idea, especially pertaining toNO and CO. For instance, both NO and CO can bind guanylate cy-

clase and thereby increase cGMP levels, triggering downstream

events like mitochondrial biogenesis (Nisoli et al., 2003; Clementi

and Nisoli, 2005; Suliman et al., 2007; Vieira et al., 2008). As NO

has higher affinity for guanylate cyclase than CO, it is likely that

its binding to guanylate cyclase pre-dominates. However, in condi-

tions when NO production is low, it is also possible that CO be-

comes the principle binding ligand for guanylate cyclase

(Piantadosi et al., 2008). Recent evidence suggests that H2S could

modulate cGMP signalling by NO, providing another point of inter-

action between the gases (Pong and Eldred, 2009). In another

example, both CO and NO prevent HIF1a stabilization (Huanget al., 1999), plausibly by creating metabolic hypoxia (Xu et al.,

2005; Zuckerbraun et al., 2007). This is a situation in which oxygen

supply to the cells is low, but cells fail to perceive this drop in oxy-

gen levels because CO and NO inhibit oxidative phosphorylation,

thereby decreasing oxygen consumption and increasing the avail-

ability of oxygen to other enzymes that regulate HIF1a stability(Xu et al., 2005). A third example of a common outcome between

CO and NO is the induction of mitochondrial membrane hyperpo-

larisation, conceivably involving the reversal of the F0F1-ATPase

(Almeida et al., 2001; Zuckerbraun et al., 2007).

Besides additive effects, the interactions could also be indepen-

dent of each other or be antagonistic in nature. For instance, CO in-

duces mitochondrial biogenesis even in eNOS or iNOS knockout

mice, suggesting that its effects are independent of NO (Suliman

etal., 2007). In terms of antagonism, studieshavedemonstrated that

thecombination of COand NOproduces less inhibition of COX activ-

ity than COalone (Pearce et al., 2008), andthat CO prevents apopto-

sis induced by the NO derivative, ONOO (Li et al., 2006).

While most of the above quoted studies focused on CO and NO,

there is also evidence, albeit less plentiful, of an interaction of

these gases with H2S. Unfortunately though, very few studies have

focused specifically on their interaction within the mitochondria.

For illustration purposes, we briefly discuss potential interactions

between the three gases with respect to one mitochondria-related

parameter and one general (non-mitochondria-specific) aspect,

namely COX inhibition and gas biosynthesis.

With respect to COX inhibition, there appears to be a potential

three-way interaction between NO, CO and H2S. CO, for instance,

could, in principle, displace NO from COX, thereby increasing the

levels of free NO, which would in turn lead to a rise in ONOO for-

mation and elevation of mitochondrial oxidative/nitrosative dam-

age (Piantadosi, 2008). Superficially, this appears to contradict

observations that COX inhibition is greater when only CO is pres-ent, as opposed to when both CO and NO are available ( Pearce

et al., 2008). Afterall, if CO indeed displaces NO from COX, then

inhibition of COX by CO should not be affected by the presence

of NO. However, assuming the hypothesis that NO is not a typical

reversibly bound competitive inhibitor holds true, such observa-

tions may not be surprising. According to the hypothesis by Pearce

et al. (2008), COX is converted to the oxidized state after NO inhi-

bition. While CO dissociates more slowly from COX than does NO,

Fig. 4. Summary of effectsof thethreegasomodulators NO, CO andH2S on themitochondria. Allthree gases modulate a finebalance between cytotoxicand cytoprotectiveevents by mediating processes such as ATP production, apoptosis and oxidative stress.



8/11

CO also has a far lower association constant for COX. Thus, when

both CO and NO are present, NO is expected to be the dominant

binding partner of COX. Although CO is, in theory, capable of dis-

placing NO from COX, it should not be able to bind COX, which is

in the oxidized state after NO binding. As a result, COX inhibition

occurs to a lesser extent when both gases are present than when

only CO is available.

Staying on the issue of COX inhibition, Cooper and Brown have

further suggested that since H2S acts as a substrate of the ETC, the

inhibition of COX by either NO or CO could prevent H2S oxidation

(Cooper and Brown, 2008). If alternative pathways to which elec-

trons from H2S oxidation can be channelled are not available, this

would result in an increase in free H2S which would further inhibit

COX. Therefore, there could potentially be an additive effect of the

three gasomodulators on COX inhibition. However, as we have dis-

cussed above, electrons may be passed onto either an alternative

oxidase (Volkel and Grieshaber, 1996) or to complex II of the ETC

(Goubern et al., 2007). It is uncertain then how relevant such an

additive effect is both in vitro and in vivo. Nonetheless, it is also

plausible that electron acceptance by these alternative pathways

can become saturated, resulting in cumulative inhibition of COX

as proposed.

Pertaining to the issue of biosynthesis, one study conducted in

macrophage cell cultures found that H2S reduces iNOS expression,

and thus decrease NO generation, via the HO-1/CO system

(Oh et al., 2006). In the absence of CO, such inhibition cannot occur.

CO alone, however, is sufficient to reduce NO production in this

system. A separate study in rats generated similar results, with

higher H2S levels being associated with decreased NO and elevated

CO levels (Li et al., 2007).

Other studies have conversely found NO to modulate CO and

H2S production. For instance, NO is known to increase CO genera-

tion by inducing HO-1 (Durante et al., 1997; Datta and Lianos,

1999; Bouton and Demple, 2000). As for H2S, studies in isolated

CBS enzyme systems have found NO to inhibit this enzyme (Taoka

and Banerjee, 2001), which presumably has the effect of decreasing

H2S production. As CO also binds CBS, in fact doing so with higheraffinity than does NO (Taoka and Banerjee, 2001), it is plausible

that CO has a similar influence over H2S biosynthesis although this

remains to be confirmed experimentally. However, these effects

again appear to be specific to the model system under study as a

separate investigation in rat smooth muscle cells found the oppo-

site effect, with NO donors increasing H2S production, plausibly, by

inducing CSE expression (Zhao et al., 2001). Alternatively, the

eventual outcome of NO on H2S generation could perhaps vary

with time. Afterall, both CBS and CSE are involved in H2S biosyn-

thesis, with CBS catalysing the formation of cystathionine from

homocysteine and serine, and CSE catalysing the next step which

generates L-cysteine and a-ketobutyrate from cystathionine. Bothenzymes then participate in the conversion ofa-ketobutyrate to

pyruvate and eventually H2S (Li and Moore, 2007). Based on the re-sults of the above studies, NO inhibits CBS, but induces CSE. In the

short-term, up-regulation of CSE would increase H2S production.

However, as the effects of upstream inhibition of CBS filter down-

stream overtime, levels of the CSE substrate, cystathionine, will

drop. Without adequate substrate, H2S synthesis can be expected

to decrease in the long run. In short, we postulate that NO may in-

crease H2S production, then decrease it subsequently. Note, how-

ever, that our hypothesis remains to be experimentally verified.

Besides the examples quoted above, there are many other plau-

sible interactions between NO, CO and H2S. For instance, their

manifold effects on apoptosis and signalling pathways such as

those involving Nrf2 and MAPK suggest potential points of inter-

section. Unfortunately, studies specifically designed to test these

interactions are lacking, and such inter-relationships remainpurely hypothetical.

6. Conclusion

This review has highlighted the influence of the three gasomod-

ulators NO, CO and H2S on the mitochondria and its related

functions such as apoptosis. Unfortunately, very few studies have

investigated the interaction between these three gases within the

mitochondria. As such, further work is needed to characterize

cross-talk between the gasomodulators and define their in vivo rel-evance. This would, among other things, require investigations into

their relative in vivo concentration, especially within the mito-

chondria, and more in-depth functional studies. Since the mito-

chondria are implicated in numerous diseases, the regulatory

functions of these gases in the mitochondria likely play a role in

influencing disease outcome. It is hopeful that with further studies,

more light will be shed on the involvement of gasomodulators in

mitochondrial function and diseases, which should map out novel

directions for pharmacological therapies.

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