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Vercellino 2022 Nat Rev Mol Cell Biol

From Bioblast
Publications in the MiPMap
Vercellino I, Sazanov LA (2022) The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol 23:141-161. doi: 10.1038/s41580-021-00415-0

ยป PMID: 34621061

Vercellino I, Sazanov Leonid A (2022) Nat Rev Mol Cell Biol

Abstract: The mitochondrial oxidative phosphorylation system is central to cellular metabolism. It comprises five enzymatic complexes and two mobile electron carriers that work in a mitochondrial respiratory chain. By coupling the oxidation of reducing equivalents coming into mitochondria to the generation and subsequent dissipation of a proton gradient across the inner mitochondrial membrane, this electron transport chain drives the production of ATP, which is then used as a primary energy carrier in virtually all cellular processes. Minimal perturbations of the respiratory chain activity are linked to diseases; therefore, it is necessary to understand how these complexes are assembled and regulated and how they function. In this Review, we outline the latest assembly models for each individual complex, and we also highlight the recent discoveries indicating that the formation of larger assemblies, known as respiratory supercomplexes, originates from the association of the intermediates of individual complexes. We then discuss how recent cryo-electron microscopy structures have been key to answering open questions on the function of the electron transport chain in mitochondrial respiration and how supercomplexes and other factors, including metabolites, can regulate the activity of the single complexes. When relevant, we discuss how these mechanisms contribute to physiology and outline their deregulation in human diseases.

โ€ข Bioblast editor: Gnaiger E

Selected quotes

  • Complex III2 accepts electrons in the form of quinol from both complex I and complex II, which in turn oxidize NADH and succinate, respectively, as well as from several dehydrogenases (dihydroorotate dehydrogenase, electron transfer flavoprotein:ubiquinone oxidoreductase, glycerol 3-phosphate dehydrogenase, choline dehydrogenase, proline dehydrogenase, sulfide:quinone oxidoreductase) also reducing ubiquinone.
  • Figure 1: The double arrow emphasizes that complex II (CII) belongs to both the Krebs cycle and the OXPHOS system. The electron carriers NADH, succinate, quinone (Q) and cytochrome c (C) are depicted as yellow ovals. NADH donates electrons to complex I (CI) and succinate donates electrons to complex II (CII), while quinone shuttles electrons from complexes I and II to complex III2 (CIII2) and cytochrome c (cyt c) shuttles electrons from complex III2 to complex IV (CIV).
  • Another way to regulate the ETC is by tuning the availability of NADH and succinate, the reducing equivalents that act as inputs to complex I and complex II.
  • Complex II couples the oxidation of succinate to fumarate (in the Krebs cycle) with the reduction of ubiquinone to ubiquinol, .. Complex II is composed of four subunits, all of which are encoded in the nuclear genome. The soluble subunits SDHA and SDHB contain the covalently bound FAD, the primary electron acceptor in the complex, and three Feโ€“S clusters (2Feโ€“2S, 4Feโ€“4S and 3Feโ€“4S), which are responsible for oxidation of succinate and electron transfer to quinone. These two matrix-located subunits are linked to the IMM via membrane-embedded subunits SDHC and SDHD. The quinone binds to and is reduced64 at the interface formed by SDHB, SDHC and SDHD,
  • The mechanism of action of complex II involves oxidation of succinate (C4H6O4) to fumarate (C4H4O4) in the SDHA subunit: the covalent bond of FAD is crucial to raise the midpoint potential of the reaction and favour succinate oxidation. While the two protons resulting from succinate oxidation are released into the matrix, the electrons are passed on to the three Feโ€“S clusters in SDHB and then on to the ubiquinone bound to SDHC and SDHD. Because the reduction of quinone involves two protons derived from the matrix side, no net proton exchange across the IMM is associated with the oxidoreduction activity of complex II.

On terminology

ยป Mitochondrial states and rates - terminology beyond MitoEAGLE 2020
For harmonization of terminology on respiratory states and rates, see

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Outdated terminology 


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Enzyme: Complex I, Complex III, Complex IV;cytochrome c oxidase, Supercomplex