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Nitric oxide as a competitive inhibitor of oxygen consumption in the mitochondrial respiratory chain
1Department of Biochemistry, University of Cambridge, Cambridge, UK.
Abstract:
Nitric oxide (NO) and its derivatives inhibit mitochondrial respiration by various means. The author and others have shown that low (nanomolar) concentrations of NO immediately, specifically and reversibly inhibit cytochrome oxidase in competition with oxygen, in isolated cytochrome oxidase, mitochondria, nerve terminals, cultured cells and tissues. Primary astrocytes and a macrophage cell line, activated by cytokines and endotoxin to express the inducible isoform of NO synthase, strongly and reversibly inhibited their own respiration and that of co-incubated cells by this means. Primary aortic endothelial cells transiently inhibited their own respiration when NO production was acutely stimulated with bradykinin or ATP, and basal NO release increased the apparent Km for oxygen of respiration in these cells. Thus the NO inhibition of cytochrome oxidase may be involved in the physiological and/or pathological regulation of respiration rate and its affinity for oxygen.
Insights
Nitric oxide (NO) reversibly inhibits mitochondrial respiration by targeting cytochrome oxidase. This mechanism may regulate cellular respiration and oxygen affinity in physiological and pathological conditions.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- Nitric oxide (NO) is known to impact cellular functions.
- Mitochondrial respiration is crucial for cellular energy production.
- Cytochrome oxidase is a key enzyme in the electron transport chain.
Purpose of the Study:
- To investigate the inhibitory effects of nitric oxide (NO) on mitochondrial respiration.
- To elucidate the mechanism by which NO affects cytochrome oxidase activity.
- To explore the physiological and pathological relevance of NO-mediated respiration inhibition.
Main Methods:
- Experiments using isolated cytochrome oxidase, mitochondria, nerve terminals, cultured cells, and tissues.
- Assessment of respiration rates and oxygen affinity in various cell types.
- Stimulation of NO production using cytokines, endotoxin, bradykinin, and ATP.
Main Results:
- Low nanomolar concentrations of NO immediately, specifically, and reversibly inhibit cytochrome oxidase.
- Activated primary astrocytes and macrophages showed significant inhibition of their own and co-incubated cells' respiration.
- Primary aortic endothelial cells exhibited transient inhibition of respiration upon NO stimulation, with basal NO release altering oxygen affinity.
Conclusions:
- Nitric oxide (NO) directly inhibits mitochondrial respiration by targeting cytochrome oxidase.
- This NO-mediated inhibition plays a role in regulating cellular respiration rate and oxygen affinity.
- The findings suggest potential involvement in both physiological and pathological processes affecting cellular energy metabolism.