Oxidation of hydrogen sulfide by human liver mitochondria (original) (raw)
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Effects of hydrogen sulfide on mitochondrial function and cellular bioenergetics
Redox Biology, 2021
Hydrogen sulfide (H 2 S) was once considered to have only toxic properties, until it was discovered to be an endogenous signaling molecule. The effects of H 2 S are dose dependent, with lower concentrations being beneficial and higher concentrations, cytotoxic. This scenario is especially true for the effects of H 2 S on mitochondrial function, where higher concentrations of the gasotransmitter inhibit the electron transport chain, and lower concentrations stimulate bioenergetics in multiple ways. Here we review the role of H 2 S in mitochondrial function and its effects on cellular physiology.
Biomolecules, 2022
The present article will not attempt to deal with sulfide per se as a signaling molecule but will aim to examine the consequences of sulfide oxidation by mitochondrial sulfide quinone reductase in mammalian cells. This oxidation appears first as a priority to avoid self-poisoning by endogenous sulfide and second to occur with the lowest ATP/O2 ratio when compared to other mitochondrial substrates. This is explained by the injection of electrons in the respiratory chain after complex I (as for succinate) and by a sulfur oxidation step implying a dioxygenase that consumes oxygen but does not contribute to mitochondrial bioenergetics. Both contribute to increase cellular oxygen consumption if sulfide is provided below its toxic level (low µM). Accordingly, if oxygen supply or respiratory chain activity becomes a limiting factor, small variations in sulfide release impact the cellular ATP/ADP ratio, a major metabolic sensor.
Abnormalities of hydrogen sulfide and glutathione pathways in mitochondrial dysfunction
Journal of Advanced Research
Background: Mitochondrial disorders are genetic diseases for which therapy remains woefully inadequate. Therapy of these disorders is particularly challenging partially due to the heterogeneity and tissue-specificity of pathomechanisms involved in these disorders. Abnormalities in hydrogen sulfide (H 2 S) metabolism are emerging as novel mechanism in mitochondrial dysfunction. However, further studies are necessary to understand the effects, protective or detrimental, of these abnormalities, and their relevance, in mitochondrial diseases. Aim of Review: To review the recent evidences of derangement of the metabolism of H 2 S, at biosynthesis or oxidation levels, in mitochondrial dysfunction, focusing specifically on the alterations of H 2 S oxidation caused by primary Coenzyme Q (CoQ) deficiency. Key Scientific Concepts of Review: Mitochondria play a key role in the regulation of H 2 S and GSH metabolism pathways. However, further studies are needed to understand the consequences of abnormalities of H 2 S and GSH synthesis on the oxidation pathway, and vice versa; and on the levels of H 2 S and GSH, their tissue-specific detrimental effects, and their role the role in mitochondrial diseases. Beside the known
Biochemistry, 2017
Hydrogen sulfide (H 2 S) is an endogenously synthesized signaling molecule that is enzymatically metabolized in mitochondria. The metabolism of H 2 S maintains optimal concentrations of the gasotransmitter and produces sulfane sulfur (S 0)-containing metabolites that may be functionally important in signaling. Sulfide:quinone oxidoreductase (SQOR) catalyzes the initial 2-electron oxidation of H 2 S to S 0 using coenzyme Q as electron acceptor in a reaction that requires a third substrate to act as the acceptor of S 0. We discovered that sulfite is a highly efficient acceptor and proposed that sulfite is the physiological acceptor in a reaction that produces thiosulfate, a known metabolic intermediate. This model has been challenged by others who assume that the intracellular concentration of sulfite is very low, a scenario postulated to favor reaction of SQOR with a considerably poorer acceptor, glutathione. In this study, we measured the intracellular concentration of sulfite and other metabolites in mammalian tissues. The values observed for sulfite in rat liver (9.2 μM) and heart (38 μM) are orders of magnitude higher than previously assumed. We discovered that the apparent kinetics of H 2 S oxidation by SQOR with glutathione as S 0 acceptor reflect contributions from other SQOR-catalyzed reactions, including a novel glutathione:CoQ reductase reaction. We used observed metabolite levels and steady-state kinetic parameters to simulate rates of H 2 S oxidation by SQOR at physiological concentrations of different S 0 acceptors. The results show that the reaction with sulfite as S 0 acceptor is a major pathway in liver and heart and provide insight into the potential dynamics of H 2 S metabolism.
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010
Sulfide (H 2 S) is an inhibitor of mitochondrial cytochrome oxidase comparable to cyanide. In this study, poisoning of cells was observed with sulfide concentrations above 20 µM. Sulfide oxidation has been shown to take place in organisms/cells naturally exposed to sulfide. Sulfide is released as a result of metabolism of sulfur containing amino acids. Although in mammals sulfide exposure is not thought to be quantitatively important outside the colonic mucosa, our study shows that a majority of mammalian cells, by means of the mitochondrial sulfide quinone reductase (SQR), avidly consume sulfide as a fuel. The SQR activity was found in mitochondria isolated from mouse kidneys, liver, and heart. We demonstrate the precedence of the SQR over the mitochondrial complex I. This explains why the oxidation of the mineral substrate sulfide takes precedence over the oxidation of other (carbon-based) mitochondrial substrates. Consequently, if sulfide delivery rate remains lower than the SQR activity, cells maintain a non-toxic sulfide concentration (b 1 µM) in their external environment. In the colonocyte cell line HT-29, sulfide oxidation provided the first example of reverse electron transfer in living cells, such a transfer increasing sulfide tolerance. However, SQR activity was not detected in brain mitochondria and neuroblastoma cells. Consequently, the neural tissue would be more sensitive to sulfide poisoning. Our data disclose new constraints concerning the emerging signaling role of sulfide.
Sulfide-inhibition of mitochondrial respiration at very low oxygen concentrations
Nitric Oxide, 2014
Our aim was to study the capacity of an immortalized cell line (AMJ2-C11) to sustain aerobic cell respiration at decreasing oxygen concentrations under continuous sulfide exposure. We assumed that the capacity of the pathway metabolizing and eliminating sulfide, which is linked to the mitochondrial respiratory chain and therefore operates under aerobic conditions, should decrease with limiting oxygen concentrations. Thus, sulfide's inhibition of cellular respiration would be dependent of the oxygen concentration in the very low range. The experiments were performed with an O2K-oxygraph (Oroboros Instruments) by suspending 0.5-1 × 10 6 cells in 2 ml of continuously stirred respiration medium at 37°C and calculating the oxygen flux (JO 2) as the negative derivative of the oxygen concentration in the medium. The cells were studied in two different metabolic states, namely under normal physiologic respiration (1) and after uncoupling of mitochondrial respiration (2). Oxygen concentration was controlled by means of a titrationinjection pump, resulting in average concentration values of 0.73 ± 0.05 μM, 3.1 ± 0.2 μM, and 6.2 ± 0.2 μM. Simultaneously we injected a 2 mM Na 2 S solution at a continuous rate of 10 μl/s in order to quantify the titration-time required to reduce the JO 2 to 50% of the initial respiratory activity. Under the lowest oxygen concentration this effect was achieved after 3.5 [0.3; 3.5] and 11.7 [6.2;21.2] min in the uncoupled and coupled state, respectively. This time was statistically significantly shorter when compared to the intermediate and the highest O 2 concentrations tested, which yielded values of 24.6[15.5;28.1] min (coupled) and 35.9[27.4;59.2] min (uncoupled), as well as 42.4 [27.5;42.4] min (coupled) and 51.5 [46.4;51.7] min (uncoupled). All data are medians [25%, and 75% percentiles]. Our results suggest that elimination of sulfide in these cells is limited by oxygen availability when approaching the anoxic condition. This property may contribute to the physiological role of sulfide as an oxygen sensor.
Hydrogen Sulfide Oxidation by Myoglobin
Journal of the American Chemical Society, 2016
Enzymes in the sulfur network generate the signaling molecule, hydrogen sulfide (H2S), from the amino acids cysteine and homocysteine. Since it is toxic at elevated concentrations, cells are equipped to clear H2S. A canonical sulfide oxidation pathway operates in mitochondria, converting H2S to thiosulfate and sulfate. We have recently discovered the ability of ferric hemoglobin to oxidize sulfide to thiosulfate and iron-bound hydropolysulfides. In this study, we report that myoglobin exhibits a similar capacity for sulfide oxidation. We have trapped and characterized iron-bound sulfur intermediates using cryo-mass spectrometry and X-ray absorption spectroscopy. Further support for the postulated intermediates in the chemically challenging conversion of H2S to thiosulfate and iron-bound catenated sulfur products is provided by EPR and resonance Raman spectroscopy in addition to density functional theory computational results. We speculate that the unusual sensitivity of skeletal mus...
Pharmacological Research, 2021
In mammalian cells enzymatic and non-enzymatic pathways produce H2S, a gaseous transmitter which recently emerged as promising therapeutic agent and modulator of mitochondrial bioenergetics. To explore this topic, the H2S donor NaHS, at micromolar concentrations, was tested on swine heart mitochondria. NaHS did not affect the F1FO-ATPase activated by the natural cofactor Mg 2 , but, when Mg 2+ was replaced by Ca 2+ , a slight 15% enzyme inhibition at 100 µM NaHS was shown. Conversely, both the NADH-O2 and succinate-O2 oxidoreductase activities were totally inhibited by 200 μM NaHS with IC50 values of 61.6±4.1 and 16.5±4.6 μM NaHS, respectively. Since the mitochondrial respiration was equally inhibited by NaHS at both first or second respiratory substrates sites, the H2S generation may prevent the electron transfer from complexes I and II to downhill respiratory chain complexes, probably because H2S competes with O2 in complex IV, thus reducing membrane potential as a consequence of the cytochrome c oxidase activity inhibition. The Complex IV blockage by H2S was consistent with the linear concentration-dependent NADH-O2 oxidoreductase inhibition and exponential succinate-O2 oxidoreductase inhibition by NaHS, whereas the coupling between substrate oxidation and phosphorylation was unaffected by NaHS. Even if H2S is known to cause sulfhydration of cysteine residues, thiol oxidizing (GSSG) or reducing (DTE) agents, did not affect the F1FO-ATPase activities and mitochondrial respiration, thus ruling out any involvement of post-translational modifications of thiols. The permeability transition pore, the lethal channel which forms when the F1FO-ATPase is stimulated by Ca 2+ , did not open in the presence of NaHS, which shows a similar effect to ruthenium red, thus suggesting a putative Ca 2+ transport cycle inhibition.
Regulation of the redox metabolome and thiol proteome by hydrogen sulfide
Critical Reviews in Biochemistry and Molecular Biology, 2021
Overproduction of reactive oxygen species and compromised antioxidant defenses perturb intracellular redox homeostasis and is associated with a myriad of human diseases as well as with the natural process of aging. Hydrogen sulfide (H 2 S), which is biosynthesized by organisms ranging from bacteria to man, influences a broad range of physiological functions. A highly touted molecular mechanism by which H 2 S exerts its cellular effects is via post-translational modification of the thiol redox proteome, converting cysteine thiols to persulfides, in a process referred to as protein persulfidation. The physiological relevance of this modification in the context of specific signal transmission pathways remains to be rigorously established, while a general protective role for protein persulfidation against hyper-oxidation of the cysteine proteome is better supported. A second mechanism by which H 2 S modulates redox homeostasis is via remodeling the redox metabolome, targeting the electron transfer chain and perturbing the major redox nodes i.e., CoQ/ CoQH 2 , NAD + /NADH and FAD/FADH 2. The metabolic changes that result from H 2 S-induced redox changes fan out from the mitochondrion to other compartments. In this review, we discuss recent developments in elucidating the roles of H 2 S and its oxidation products on redox homeostasis and its role in protecting the thiol proteome.