Sulfide affects the mitochondrial respiration, the Ca2+-activated F1FO-ATPase activity and the permeability transition pore but does not change the Mg2+-activated F1FO-ATPase activity in swine heart mitochondria. (April 2021)

• Record Type: Journal Article
• Authors: Nesci, Salvatore; Algieri, Cristina; Trombetti, Fabiana; Ventrella, Vittoria; Fabbri, Micaela; Pagliarani, Alessandra
• Is Part Of: Pharmacological research. Volume 166(2021)
• Publication Date: 2021-04
• Subjects: H2S -- Mitochondria -- Mitochondrial respiration -- F1FO-ATPase -- Permeability transition pore -- Cofactors; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105495
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: In mammalian cells enzymatic and non-enzymatic pathways produce H2 S, a gaseous transmitter which recently emerged as promising therapeutic agent and modulator of mitochondrial bioenergetics. To explore this topic, the H2 S donor NaHS, at micromolar concentrations, was tested on swine heart mitochondria. NaHS did not affect the F1 FO -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 H2 S generation may prevent the electron transfer from complexes I and II to downhill respiratory chain complexes, probably because H2 S 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 H2 S 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 H2 S is known to cause sulfhydration of cysteine residues, thiol oxidizing (GSSG) or reducing (DTE) agents, did not affect the F1 FO -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 F1 FO -ATPase is stimulated by Ca 2+, did not open in the presence of NaHS, which showed a similar effect to ruthenium red, thus suggesting a putative Ca 2+ transport cycle inhibition. Graphical Abstract: ga1 Highlights: The mitochondrial respiration inhibition by H2 S mainly occurs at C II and C IV. The F1 FO -ATPase is only inhibited by 100 µM NaHS when activated by Ca 2+ . The PTP desensitization by H2 S can be related to an impaired Ca 2 + cycle. Post-translational modifications of thiols are not involved in the H2 S effects.