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Peroxynitrite formed by mitochondrial NO synthase promotes mitochondrial Ca2+ release
U Bringold1, P Ghafourifar, C Richter
1Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), Zurich.
Free Radical Biology & Medicine
|October 18, 2000
Summary
Mitochondria regulate intracellular calcium (Ca2+) levels. Intramitochondrial peroxynitrite (ONOO-) formation stimulates a specific calcium release pathway, preventing mitochondrial overload.
Area of Science:
- Mitochondrial biology
- Cellular physiology
- Biochemistry
Background:
- Mitochondria maintain intracellular calcium (Ca2+) homeostasis through distinct uptake and release pathways.
- The molecular mechanisms of mitochondrial Ca2+ release are not fully understood but involve thiol cross-linking and NAD+ hydrolysis.
- Peroxynitrite (ONOO-), formed from superoxide (O2-) and nitric oxide (NO*), can induce thiol cross-linking and NAD+ hydrolysis.
Purpose of the Study:
- To investigate the role of intramitochondrially generated peroxynitrite (ONOO-) in stimulating mitochondrial Ca2+ release.
- To elucidate the feedback loop involving nitric oxide synthase (mtNOS), Ca2+, and ONOO- in mitochondrial Ca2+ regulation.
Main Methods:
- Studying isolated mitochondria.
- Measuring mitochondrial Ca2+ uptake and release.
- Assessing peroxynitrite (ONOO-) formation.
- Investigating nitric oxide synthase (mtNOS) activity.
Main Results:
- Mitochondria possess an NO synthase (mtNOS) stimulated by Ca2+ and produce superoxide (O2-).
- Intramitochondrial formation of peroxynitrite (ONOO-) was observed upon Ca2+ uptake.
- Peroxynitrite (ONOO-) stimulated a specific, NAD+-dependent Ca2+ release from mitochondria.
Conclusions:
- Intramitochondrially formed peroxynitrite (ONOO-) is a key regulator of mitochondrial Ca2+ release.
- A feedback loop involving Ca2+ uptake, mtNOS stimulation, ONOO- production, and subsequent Ca2+ release exists.
- This feedback mechanism prevents mitochondrial Ca2+ overload.