Hydrogen sulfide-mediated stimulation of mitochondrial electron transport involves inhibition of the mitochondrial phosphodiesterase 2A, elevation of cAMP and activation of protein kinase A

Abstract

Although hydrogen sulfide (H₂S) is generally known as a mitochondrial poison, recent studies show that lower concentrations of H₂S play a physiological role in the stimulation of mitochondrial electron transport and cellular bioenergetics. This effect involves electron donation at Complex II. Other lines of recent studies demonstrated that one of the biological actions of H₂S involves inhibition of cAMP and cGMP phosphodiesterases (PDEs). Given the emerging functional role of the mitochondrial isoform of cAMP PDE (PDE2A) in the regulation of mitochondrial function the current study investigated whether cAMP-dependent mechanisms participate in the stimulatory effect of NaHS on mitochondrial function. In isolated rat liver mitochondria, partial digestion studies localized PDE2A into the mitochondrial matrix. NaHS exerted a concentration-dependent inhibitory effect on recombinant PDE2A enzyme in vitro. Moreover, NaHS induced an elevation of cAMP levels when added to isolated mitochondria and stimulated the mitochondrial electron transport. The latter effect was inhibited by Rp-cAMP, an inhibitor of the cAMP-dependent protein kinase (PKA). The current findings suggest that the direct electron donating effect of NaHS is amplified by an intramitochondrial cAMP system, which may involve the inhibition of PDE2A and subsequent, cAMP-mediated stimulation of PKA.

Keywords: 3-isobutyl-1-methylxanthine (CID: 3758); 8-bromo cyclic AMP sodium salt (CID: 1913); 9-(2-hydroxy-3-nonyl)adenine (CID: 3206); ADP; ATP; Adenosine 5′-diphosphate; Adenosine 5′-triphosphate; Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; CcOX, Complex IV; Cyc C; Cytochrome C; Cytochrome c Oxidase, mitochondrial complex IV; FCCP; H(2)S; Hydrogen sulfide; Isolated mitochondria; OCR; Oxygen Consumption Rate; PDE; PKA; Phosphodiesterase; Rp-adenosine 3′,5′-cyclic monophosphorothioate (CID: 16218857); SQR; Sulfide:quinone oxidoreductase; adenosine 5′-diphosphate (CID: 6022); adenosine 5′-triphosphate (CID: 11050836); cAMP; cAMP-dependent protein kinase/Protein Kinase A; carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (CID: 3330); hydrogen sulfide (CID: 402); sodium hydrogen sulfide (CID: 28015).