Nitric oxide in mitochondria: Formation and consequences
Richter, C. and Ghafourifar, P.
Laboratory of Biochemistry I, Swiss Federal Institute of Technology (ETH),
Universitätsstr. 16, CH-8092 Zürich, Switzerland
Nitric oxide (nitrogen monoxide, NO) is a molecule of prime importance in biology. It is synthesized by a family of enzymes (nitric oxide synthases, NOS), three classes of which (neuronal, endothelial, and inducible NOS) are well characterized by now. The main targets of NO are heme proteins and thiols, but nitric oxide also readily combines with superoxide to produce the highly reactive peroxynitrite (ONOO-). We have reported on two important actions of NO and ONOO- when added to mitochondria. Firstly, NO binds to cytochrome oxidase and thereby inhibits mitochondrial respiration. As a consequence, NO lowers the mitochondrial membrane potential and thereby promotes Ca2+ release from mitochondria. This principle is used in cellular signalling, e.g. in glucose-induced insulin secretion [1]. Secondly, ONOO- activates the ADP-ribose-dependent Ca2+ release pathway from mitochondria by oxidizing vicinal thiols important for ADP-ribose provision.
We have identified a mitochondrial NOS (mtNOS) [2]. The enzyme uses L-arginine (L-arg) to produce NO and L-citrulline, and is Ca2+-dependent. L-arg analogues, N
-monomethyl-L-arg and N-nitro-L-arg, inhibit the enzyme, and D-arginine is not a substrate for it. MtNOS activity is associated with the inner mitochondrial membrane. In intact, succinate-energized mitochondria, the enzyme is constituently active and exerts substantial control over mitochondrial respiration and membrane potential. The activity is further stimulated when Ca2+ is taken up by mitochondria. We suggest that the existence of mtNOS and ist Ca2+-dependency are highly relevant for mitochondrial functioning.
[1] Spinas, G.A., Laffranchi, R., Francoys, I., David, I., Richter, C., Reinecke, M. (1988) The early phase of glucose-stiulated insulin secretion requires nitric oxide. Diabetologia 41: in press
[2] Ghafourifar, P. and Richter, C. (1997) Nitric oxide synthase activity in mitochondria. FEBS Lett. 418: 291-296
| LOCATION |
DATE |
TIME |
| Lecture Hall II |
Wednesday, April 8 |
10:10 am |