Abstract
Complex I (NADH:ubiquinone oxidoreductase) is critical for respiration in mammalian mitochondria. It oxidizes NADH produced by the Krebs' tricarboxylic acid cycle and β-oxidation of fatty acids, reduces ubiquinone, and transports protons to contribute to the proton-motive force across the inner membrane. Complex I is also a significant contributor to cellular oxidative stress. In complex I, NADH oxidation by a flavin mononucleotide, followed by intramolecular electron transfer along a chain of iron–sulfur clusters, delivers electrons and energy to bound ubiquinone. Either at cluster N2 (the terminal cluster in the chain) or upon the binding/reduction/dissociation of ubiquinone/ubiquinol, energy from the redox process is captured to initiate long-range energy transfer through the complex and drive proton translocation. This review focuses on current knowledge of how the redox reaction and proton transfer are coupled, with particular emphasis on the formation and role of semiquinone intermediates in both energy transduction and reactive oxygen species production. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Highlights
Introduction to complex IComplex I (NADH:ubiquinone oxidoreductase) [1] plays a central role in the cellular metabolism of humans and many other organisms
This review focuses on current knowledge of how the redox reaction and proton transfer are coupled, with particular emphasis on the formation and role of semiquinone intermediates in both energy transduction and reactive oxygen species production
In this review we focus on the redox chemistry of complex I, and on current knowledge pertaining to the mechanism by which the redox energy is captured and used to initiate proton translocation
Summary
Complex I (NADH:ubiquinone oxidoreductase) [1] plays a central role in the cellular metabolism of humans and many other organisms. The two electrons from NADH oxidation are transferred through the enzyme and used to reduce ubiquinone to ubiquinol in the inner mitochondrial membrane, supplying the rest of the electron transport chain with electrons for the reduction of oxygen to water. Reactive oxygen species production by complex I is an important contributor to mitochondrial and cellular oxidative stress [2]. Complex I dysfunctions are caused by genetic, environmental, and pathological factors, and have been linked to both impaired catalytic ability and enhanced superoxide production [3] Their molecular, mechanistic, and energetic consequences remain poorly understood, highlighting the need for improved basic knowledge of the enzyme's molecular structure and function. We close by considering how current knowledge of the redox mechanism of complex I contributes to understanding its mechanisms of energy transduction and reactive oxygen species production
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