Mammalian NADH:ubiquinone oxidoreductase (Complex I) and nicotinamide nucleotide transhydrogenase (Nnt) together regulate the mitochondrial production of H2O2—Implications for their role in disease, especially cancer
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- 作者：Simon P. J. Albracht (1) s.p.j.albracht@uva.nl
Alfred J. Meijer (2)
Jan Rydstr?m (3) - 关键词：NADH ; ubiquinone oxidoreductase – Transhydrogenase – Reactive oxygen species (ROS) – Cancer
- 刊名：Journal of Bioenergetics and Biomembranes
- 出版年：2011
- 出版时间：October 2011
- 年：2011
- 卷：43
- 期：5
- 页码：541-564
- 全文大小：778.2 KB
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- 刊物类别：Chemistry and Materials Science
- 刊物主题：Chemistry
Bioorganic Chemistry
Biochemistry
Animal Anatomy, Morphology and Histology
Animal Biochemistry
Organic Chemistry - 出版者：Springer New York
- ISSN：1573-6881
文摘
Mammalian NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial inner membrane catalyzes the oxidation of NADH in the matrix. Excess NADH reduces nine of the ten prosthetic groups of the enzyme in bovine-heart submitochondrial particles with a rate of at least 3,300 s?1. This results in an overall NADH→O2 rate of ca. 150 s?1. It has long been known that the bovine enzyme also has a specific reaction site for NADPH. At neutral pH excess NADPH reduces only three to four of the prosthetic groups in Complex I with a rate of 40 s?1 at 22 °C. The reducing equivalents remain essentially locked in the enzyme because the overall NADPH→O2 rate (1.4 s?1) is negligible. The physiological significance of the reaction with NADPH is still unclear. A number of recent developments has revived our thinking about this enigma. We hypothesize that Complex I and the Δp-driven nicotinamide nucleotide transhydrogenase (Nnt) co-operate in an energy-dependent attenuation of the hydrogen-peroxide generation by Complex I. This co-operation is thought to be mediated by the NADPH/NADP+ ratio in the vicinity of the NADPH site of Complex I. It is proposed that the specific H2O2 production by Complex I, and the attenuation of it, is of importance for apoptosis, autophagy and the survival mechanism of a number of cancers. Verification of this hypothesis may contribute to a better understanding of the regulation of these processes.