S-nitrosothiol inhibition of mitochondrial complex I causes a reversible increase in mitochondrial hydrogen peroxide production.
We found that reversible inactivation of mitochondrial complex I by S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in isolated rat heart mitochondria resulted in a three-fold increase in H2O2 production, when mitochondria were respiring on pyruvate and malate, (but not when respiring on succinate or in the absence of added respiratory substrate). The inactivation of complex I and the increased H2O2 production were present in mitochondria washed free of SNAP or NO, but were partially reversed by light or dithiothreitol, treatments known to reverse S-nitrosation. Specific inhibition of complex I with rotenone increased H2O2 production to a similar extent as that caused by SNAP. The results suggest that S-nitrosation of complex I can reversibly increase oxidant production by mitochondria, which is potentially important in cell signalling and/or pathology.
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. vb207@mole.bio.cam.ac.uk
Vilmante
V
Borutaite
Guy C
GC
Brown
D000818:Animals; D019069:Cell Respiration; D004229:Dithiothreitol / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D008293:Malates / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D019802:Succinic Acid / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
D008293:Malates; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D014475:Uncoupling Agents; D012402:Rotenone; D009569:Nitric Oxide; C030298:malic acid; D019289:Pyruvic Acid; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I; D010396:Penicillamine; D004229:Dithiothreitol