Peroxynitrite formed by mitochondrial NO synthase promotes mitochondrial Ca2+ release.
Mitochondria contribute to the maintenance of the intracellular Ca2+ homeostasis by taking up and releasing the cation via separate and specific pathways. The molecular details of the release pathway are elusive but its stimulation by the cross-linking of some vicinal thiols and consequently NAD+ hydrolysis are known. Thiol cross-linking and NAD+ hydrolysis can be achieved by addition of peroxynitrite (ONOO-), the product of the reaction between superoxide (O2-) and nitric oxide (nitrogen monoxide, NO*) to mitochondria. Mitochondria contain an NO synthase (mtNOS), which is stimulated by Ca2+, and are a copious source of O2-. We show here that intramitochondrially formed ONOO- stimulates the specific, NAD+-linked Ca2+ release from mitochondria. Our findings that upon Ca2+ uptake mtNOS is stimulated, that ONOO- is formed, and that Ca2+ is subsequently released from intact mitochondria suggest the existence of a feedback loop, which prevents overloading of mitochondria with Ca2+.
Bringold
U
U
Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), Zurich.
Ghafourifar
P
P
Richter
C
C
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005246:Feedback; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008665:Metalloporphyrins / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D016166:Free Radical Scavengers; D005609:Free Radicals; D008665:Metalloporphyrins; D009566:Nitrates; D016877:Oxidants; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D012402:Rotenone; D009243:NAD; C039642:peroxynitric acid; D019323:omega-N-Methylarginine; D020122:tert-Butylhydroperoxide; D019001:Nitric Oxide Synthase; D002118:Calcium