title: 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.
abstract: 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.
authors: Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, NL-1098 XH, Amsterdam, The Netherlands. s.p.j.albracht@uva.nl
authors: Simon P J
authors: SP
authors: Albracht
authors: Alfred J
authors: AJ
authors: Meijer
authors: Jan
authors: J
authors: Rydström
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008322:Mammals; D009250:NADP Transhydrogenases / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology*
chemical_list: D009363:Neoplasm Proteins; D006861:Hydrogen Peroxide; D009250:NADP Transhydrogenases; D042967:Electron Transport Complex I