The assembly, regulation and function of the mitochondrial respiratory chain

Nature Reviews Molecular Cell Biology - Tập 23 Số 2 - Trang 141-161 - 2022
Irene Vercellino1, Leonid A. Sazanov1
1Institute of Science and Technology Austria, Klosterneuburg, Austria

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Nicholls, D. Bioenergetics - 4th Edition (Academic Press, 2013).

Green, D. E. & Tzagoloff, A. The mitochondrial electron transfer chain. Arch. Biochem. Biophys. 116, 293–304 (1966).

Krebs, H. A. & Johnson, W. A. The role of citric acid in intermediate metabolism in animal tissues. Enzymologia 4, 148–156 (1937).

Jones, A. J. Y., Blaza, J. N., Varghese, F. & Hirst, J. Respiratory complex I in Bos taurus and Paracoccus denitrificans pumps four protons across the membrane for every NADH oxidized. J. Biol. Chem. 292, 4987–4995 (2017).

Mitchell, P. Possible molecular mechanisms of the protonmotive function of cytochrome systems. J. Theor. Biol. 62, 327–367 (1976).

Trumpower, B. L. The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc1 complex. J. Biol. Chem. 265, 11409–11412 (1990).

Maréchal, A. et al. A common coupling mechanism for A-type heme-copper oxidases from bacteria to mitochondria. Proc. Natl Acad. Sci. USA 117, 9349–9355 (2020).

Rizwan, M., Rasheed, H. Al, & Tarjan, G. Succinate dehydrogenase complex: an updated review. Arch. Pathol. Lab. Med. 142, 1564–1570 (2018).

Wang, Y. & Hekimi, S. Understanding ubiquinone. Trends Cell Biol. 26, 367–378 (2016).

Alcázar-Fabra, M., Rodríguez-Sánchez, F., Trevisson, E. & Brea-Calvo, G. Primary coenzyme Q deficiencies: a literature review and online platform of clinical features to uncover genotype-phenotype correlations. Free Radic. Biol. Med. 167, 141–180 (2021).

Mitchell, P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191, 144–148 (1961).

Tang, J. X., Thompson, K., Taylor, R. W. & Oláhová, M. Mitochondrial OXPHOS biogenesis: co-regulation of protein synthesis, import, and assembly pathways. Int. J. Mol. Sci. 21, 1–32 (2020).

Cogliati, S., Lorenzi, I., Rigoni, G., Caicci, F. & Soriano, M. E. Regulation of mitochondrial electron transport chain assembly. J. Mol. Biol. 430, 4849–4873 (2018).

Priesnitz, C. & Becker, T. Pathways to balance mitochondrial translation and protein import. Genes. Dev. 32, 1285–1296 (2018).

Cardenas-Rodriguez, M., Chatzi, A. & Tokatlidis, K. Iron–sulfur clusters: from metals through mitochondria biogenesis to disease. J. Biol. Inorg. Chem. 23, 509–520 (2018).

Swenson, S. A. et al. From synthesis to utilization: the ins and outs of mitochondrial heme. Cells 9, 579 (2020).

Pierron, D. et al. Cytochrome c oxidase: evolution of control via nuclear subunit addition. Biochim. Biophys. Acta 1817, 590–597 (2012).

Xia, D. et al. Structural analysis of cytochrome bc1 complexes: implications to the mechanism of function. Biochim. Biophys. Acta 1827, 1278–1294 (2013).

Stroud, D. A. et al. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 538, 123–126 (2016).

Ghezzi, D. & Zeviani, M. Assembly factors of human mitochondrial respiratory chain complexes: physiology and pathophysiology. Adv. Exp. Med. Biol. 748, 65–106 (2012).

Páleníková, P. et al. Duplexing complexome profiling with SILAC to study human respiratory chain assembly defects. Biochim.Biophys. Acta Bioenerg. 1862, 148395 (2021).

Maldonado, M., Guo, F. & Letts, J. A. Atomic structures of respiratory complex III2, complex IV, and supercomplex III2-IV from vascular plants. eLife 10, 1–34 (2021).

Letts, J. A., Fiedorczuk, K., Degliesposti, G., Skehel, M. & Sazanov, L. A. Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk. Mol. Cell 75, 1131–1146.e6 (2019).

Letts, J. A., Fiedorczuk, K. & Sazanov, L. A. The architecture of respiratory supercomplexes. Nature 537, 644–648 (2016).

Wu, M., Gu, J., Guo, R., Huang, Y. & Yang, M. Structure of mammalian respiratory supercomplex I1III2IV1. Cell 167, 1598–1609.e10 (2016).

Guo, R., Zong, S., Wu, M., Gu, J. & Yang, M. Architecture of human mitochondrial respiratory megacomplex I2III2IV2. Cell 170, 1247–1257 (2017).

Gu, J. et al. The architecture of the mammalian respirasome. Nature 537, 639–643 (2016). This, along with Letts et al. (2016), reported the first structure of the mammalian respirasome.

Rathore, S. et al. Cryo-EM structure of the yeast respiratory supercomplex. Nat. Struct. Mol. Biol. 26, 50–57 (2019).

Hartley, A. M. et al. Structure of yeast cytochrome c oxidase in a supercomplex with cytochrome bc1. Nat. Struct. Mol. Biol. 26, 78–83 (2019). This, along with Rathore et al., reported the first structure of the mitochondrial yeast supercomplex CIII2CIV.

Hartley, A. M., Meunier, B., Pinotsis, N. & Maréchal, A. Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes. Proc. Natl Acad. Sci. USA 117, 9329–9337 (2020).

Schägger, H. & Pfeiffer, K. Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J. 19, 1777–1783 (2000). First characterization of supercomplexes.

Moe, A. et al. Cryo-EM structure and kinetics reveal electron transfer by 2D diffusion of cytochrome c in the yeast III-IV respiratory supercomplex. Proc. Natl Acad. Sci. USA 118, e2021157118 (2021).

Lobo-Jarne, T. et al. Multiple pathways coordinate assembly of human mitochondrial complex IV and stabilization of respiratory supercomplexes. EMBO J. 39, e103912 (2020).

Protasoni, M. et al. Respiratory supercomplexes act as a platform for complex III-mediated maturation of human mitochondrial complexes I and IV. EMBO J. 39, e102817 (2020).

Fernandez-Vizarra, E. & Zeviani, M. Mitochondrial disorders of the OXPHOS system. FEBS Lett. 595, 1062–1106 (2020).

Bratic, A. & Larsson, N. G. The role of mitochondria in aging. J. Clin. Invest. 123, 951–957 (2013).

Mukherjee, S. & Ghosh, A. Molecular mechanism of mitochondrial respiratory chain assembly and its relation to mitochondrial diseases. Mitochondrion 53, 1–20 (2020).

Signes, A. & Fernandez-Vizarra, E. Assembly of mammalian oxidative phosphorylation complexes I–V and supercomplexes. Essays Biochem. 62, 255–270 (2018).

Grba, D. N. & Hirst, J. Mitochondrial complex I structure reveals ordered water molecules for catalysis and proton translocation. Nat. Struct. Mol. Biol. 27, 892–900 (2020).

Kampjut, D. & Sazanov, L. A. The coupling mechanism of mammalian respiratory complex I. Science 370, eabc4209 (2020). Structure-based description of the coupling mechanism of mammalian complex I.

Gutiérrez-Fernández, J. et al. Key role of quinone in the mechanism of respiratory complex I. Nat. Commun. 11, 4135 (2020).

Zhou, L. & Sazanov, L. A. Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase. Science 365, eaaw9144 (2019).

Pinke, G., Zhou, L. & Sazanov, L. A. Cryo-EM structure of the entire mammalian F-type ATP synthase. Nat. Struct. Mol. Biol. 27, 1077–1085 (2020).

Spikes, T. E., Montgomery, M. G. & Walker, J. E. Structure of the dimeric ATP synthase from bovine mitochondria. Proc. Natl Acad. Sci. USA 117, 23519–23526 (2020).

Fiedorczuk, K. et al. Atomic structure of the entire mammalian mitochondrial complex I. Nature 538, 406–410 (2016).

Zhu, J., Vinothkumar, K. R. & Hirst, J. Structure of mammalian respiratory complex I. Nature 536, 354–358 (2016).

Chomyn, A. et al. Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase. Nature 314, 592–597 (1985).

Chomyn, A. et al. URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit. Science 234, 614–618 (1986).

Baradaran, R., Berrisford, J. M., Minhas, G. S. & Sazanov, L. A. Crystal structure of the entire respiratory complex I. Nature 494, 443–448 (2013).

Formosa, L. E. et al. Dissecting the roles of mitochondrial complex I intermediate assembly complex factors in the biogenesis of complex I. Cell Rep. 31, 107541 (2020).

Guerrero-Castillo, S. et al. The assembly pathway of mitochondrial respiratory chain complex I. Cell Metab. 25, 128–139 (2017).

Formosa, L. E. et al. Optic atrophy–associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I. Proc. Natl Acad. Sci. USA 118, e2019665118 (2021).

Sánchez-Caballero, L. et al. TMEM70 functions in the assembly of complexes I and V. Biochim. Biophys. Acta Bioenerg. 1861, 148202 (2020).

Carroll, J., He, J., Ding, S., Fearnley, I. M. & Walker, J. E. TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I. Proc. Natl Acad. Sci. USA 118, e2100558118 (2021).

Pierrel, F. et al. Coa1 links the Mss51 post-translational function to Cox1 cofactor insertion in cytochrome c oxidase assembly. EMBO J. 26, 4335–4346 (2007).

Leif, H., Sled, V. D., Ohnishi, T., Weiss, H. & Friedrich, T. Isolation and characterization of the proton-translocating NADH:ubiquinone oxidoreductase from Escherichia coli. Eur. J. Biochem. 230, 538–548 (1995).

Sazanov, L. A. & Hinchliffe, P. Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science 311, 1430–1436 (2006).

Verkhovskaya, M. L., Belevich, N., Euro, L., Wikström, M. & Verkhovsky, M. I. Real-time electron transfer in respiratory complex I. Proc. Natl Acad. Sci. USA 105, 3763–3767 (2008).

Berrisford, J. M. & Sazanov, L. A. Structural basis for the mechanism of respiratory complex I. J. Biol. Chem. 284, 29773–29783 (2009).

Parey, K. et al. Cryo-EM structure of respiratory complex I at work. eLife 7, e39213 (2018).

Bridges, H. R. et al. Structure of inhibitor-bound mammalian complex I. Nat. Commun. 11, 1–11 (2020).

Verkhovskaya, M. & Bloch, D. A. Energy-converting respiratory complex I: on the way to the molecular mechanism of the proton pump. Int. J. Biochem. Cell Biol. 45, 491–511 (2013).

Kaila, V. R. I. Long-range proton-coupled electron transfer in biological energy conversion: towards mechanistic understanding of respiratory complex I. J. R. Soc. Interface 15, 20170916 (2018).

Iverson, T. M. Catalytic mechanisms of complex II enzymes: a structural perspective. Biochim. Biophys. Acta Bioenerg. 1827, 648–657 (2013).

Sun, F. et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121, 1043–1057 (2005).

Moosavi, B., Berry, E. A., Zhu, X. L., Yang, W. C. & Yang, G. F. The assembly of succinate dehydrogenase: a key enzyme in bioenergetics. Cell. Mol. Life Sci. 76, 4023–4042 (2019).

Huang, L. S. et al. 3-Nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidation by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. J. Biol. Chem. 281, 5965–5972 (2006).

Scalliet, G. et al. Mutagenesis and functional studies with succinate dehydrogenase inhibitors in the wheat pathogen Mycosphaerella graminicola. PLoS ONE 7, e35429 (2012).

Ruprecht, J. et al. Perturbation of the quinone-binding site of complex II alters the electronic properties of the proximal [3Fe-4S] iron-sulfur cluster. J. Biol. Chem. 286, 12756–12765 (2011).

Yankovskaya, V. et al. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299, 700–704 (2003).

Oyedotun, K. S., Sit, C. S. & Lemire, B. D. The Saccharomyces cerevisiae succinate dehydrogenase does not require heme for ubiquinone reduction. Biochim. Biophys. Acta Bioenerg. 1767, 1436–1445 (2007).

Blaut, M. et al. Fumarate reductase mutants of Escherichia coli that lack covalently bound flavin. J. Biol. Chem. 264, 13599–13604 (1989).

Xia, D. et al. Crystal structure of the cytochrome bc1 complex from bovine heart mitochondria. Science 277, 60–66 (1997).

Xia, D., Esser, L., Yu, L. & Yu, C. A. Structural basis for the mechanism of electron bifurcation at the quinol oxidation site of the cytochrome bc1 complex. Photosynthesis Res. 92, 17–34 (2007).

Sarewicz, M. & Osyczka, A. Electronic connection between the quinone and cytochrome c redox pools and its role in regulation of mitochondrial electron transport and redox signaling. Physiol. Rev. 95, 219–243 (2015).

Cooley, J. W., Roberts, A. G., Bowman, M. K., Kramer, D. M. & Daldal, F. The raised midpoint potential of the [2Fe2S] cluster of cytochrome bc1 is mediated by both the Qo site occupants and the head domain position of the Fe-S protein subunit. Biochemistry 43, 2217–2227 (2004).

Cooley, J. W., Ohnishi, T. & Daldal, F. Binding dynamics at the quinone reduction (Qi) site influence the equilibrium interactions of the iron sulfur protein and hydroquinone oxidation (Qo) site of the cytochrome bc1 complex. Biochemistry 44, 55 (2005).

Cooley, J. W., Lee, D. W. & Daldal, F. Across membrane communication between the Qo and Q1 active sites of cytochrome bc1. Biochemistry 48, 1888–1899 (2009).

Dikanov, S. A. et al. Identification of hydrogen bonds to the Rieske cluster through the weakly coupled nitrogens detected by electron spin echo envelope modulation spectroscopy. J. Biol. Chem. 281, 27416–27425 (2006).

Sarewicz, M., Dutka, M., Pintscher, S. & Osyczka, A. Triplet state of the semiquinone-Rieske cluster as an intermediate of electronic bifurcation catalyzed by cytochrome bc1. Biochemistry 52, 6388–6395 (2013).

McCurley, J. P., Miki, T., Yu, L. & Yu, C. A. EPR characterization of the cytochrome b-c1 complex from Rhodobacter sphaeroides. BBA Bioenerg. 1020, 176–186 (1990).

Sarewicz, M., Borek, A., Daldal, F., Froncisz, W. & Osyczka, A. Demonstration of short-lived complexes of cytochrome c with cytochrome bc1 by EPR spectroscopy: implications for the mechanism of interprotein electron transfer. J. Biol. Chem. 283, 24826–24836 (2008).

Zong, S. et al. UQCRFS1N assembles mitochondrial respiratory complex-III into an asymmetric 21-subunit dimer. Protein Cell 9, 586–591 (2018).

Ndi, M., Marin-Buera, L., Salvatori, R., Singh, A. P. & Ott, M. Biogenesis of the bc1 complex of the mitochondrial respiratory chain. J. Mol. Biol. 430, 3892–3905 (2018).

Hildenbeutel, M. et al. Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondrial translation. J. Cell Biol. 205, 511–524 (2014).

Gruschke, S. et al. The Cbp3-Cbp6 complex coordinates cytochrome b synthesis with bc1 complex assembly in yeast mitochondria. J. Cell Biol. 199, 137–150 (2012).

Stephan, K. & Ott, M. Timing of dimerization of the bc1 complex during mitochondrial respiratory chain assembly. Biochim. Biophys. Acta Bioenerg. 1861, 148177 (2020).

Sánchez, E. et al. LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial complex III assembly in human cells. Biochim. Biophys. Acta 1827, 285–293 (2013).

Fernandez-Vizarra, E. et al. Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Hum. Mol. Genet. 16, 1241–1252 (2007).

Wagener, N., Ackermann, M., Funes, S. & Neupert, W. A pathway of protein translocation in mitochondria mediated by the AAA-ATPase Bcs1. Mol. Cell 44, 191–202 (2011).

Tang, W. K. et al. Structures of AAA protein translocase Bcs1 suggest translocation mechanism of a folded protein. Nat. Struct. Mol. Biol. 27, 202–209 (2020).

Zara, V., Conte, L. & Trumpower, B. L. Evidence that the assembly of the yeast cytochrome bc1 complex involves the formation of a large core structure in the inner mitochondrial membrane. FEBS J. 276, 1900–1914 (2009).

Bottani, E. et al. TTC19 plays a husbandry role on UQCRFS1 turnover in the biogenesis of mitochondrial respiratory complex III. Mol. Cell 67, 96–105.e4 (2017).

Ghezzi, D. et al. Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat. Genet. 43, 259–263 (2011).

Berry, E. A., De Bari, H. & Huang, L. S. Unanswered questions about the structure of cytochrome bc1 complexes. Biochim. Biophys. Acta 1827, 1258–1277 (2013).

Fernandez-Vizarra, E. & Zeviani, M. Mitochondrial complex III Rieske Fe-S protein processing and assembly. Cell Cycle 17, 681–687 (2018).

Vercellino, I. & Sazanov, L. Structure and assembly of mammalian mitochondrial supercomplex CIII2CIV. Nature https://doi.org/10.1038/s41586-021-03927-z (2021). First structure of mammalian supercomplex CIII2CIV.

Zhang, S. et al. Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Nat. Commun. 11, 1–16 (2020).

Yoshikawa, S. & Shimada, A. Reaction mechanism of cytochrome c oxidase. Chem. Rev. 115, 1936–1989 (2015).

Timón-Gómez, A. et al. Mitochondrial cytochrome c oxidase biogenesis: recent developments. Semin. Cell Dev. Biol. 76, 163–178 (2018).

Shinzawa-Itoh, K. et al. Structures and physiological roles of 13 integral lipids of bovine heart cytochrome c oxidase. EMBO J. 26, 1713–1725 (2007).

Zong, S. et al. Structure of the intact 14-subunit human cytochrome c oxidase. Cell Res. 28, 1026–1034 (2018).

Watson, S. A. & McStay, G. P. Functions of cytochrome c oxidase assembly factors. Int. J. Mol. Sci. 21, 1–18 (2020).

Vidoni, S. et al. MR-1S interacts with PET100 and PET117 in module-based assembly of human cytochrome c oxidase. Cell Rep. 18, 1727–1738 (2017).

Calvo, E. et al. Functional role of respiratory supercomplexes in mice: SCAF1 relevance and segmentation of the Qpool. Sci. Adv. 6, eaba7509 (2020). SCAF1-mediated modulation of supercomplexes assembly in mice.

Diaz, F., Fukui, H., Garcia, S. & Moraes, C. T. Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol. Cell. Biol. 26, 4872–4881 (2006).

Čunátová, K. et al. Loss of COX4I1 leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis. Cells 10, 369 (2021).

Yoshikawa, S., Muramoto, K. & Shinzawa-Itoh, K. Proton-pumping mechanism of cytochrome c oxidase. Annu. Rev. Biophys. 40, 205–223 (2011).

Abbas, Y. M., Wu, D., Bueler, S. A., Robinson, C. V. & Rubinstein, J. L. Structure of V-ATPase from the mammalian brain. Science 367, 1240–1246 (2020).

Morales-Rios, E. et al. Purification, characterization and crystallization of the F-ATPase from Paracoccus denitrificans. Open. Biol. https://doi.org/10.1098/rsob.150119 (2015).

Hahn, A., Vonck, J., Mills, D. J., Meier, T. & Kühlbrandt, W. Structure, mechanism, and regulation of the chloroplast ATP synthase. Science 360, eaat4318 (2018).

Grüber, G., Manimekalai, M. S. S., Mayer, F. & Müller, V. ATP synthases from archaea: the beauty of a molecular motor. Biochim. Biophys. Acta 1837, 940–952 (2014).

He, J. et al. Assembly of the membrane domain of ATP synthase in human mitochondria. Proc. Natl Acad. Sci. USA 115, 2988–2993 (2018).

He, J. et al. Assembly of the peripheral stalk of ATP synthase in human mitochondria. Proc. Natl Acad. Sci. USA 117, 29602–29608 (2020).

Blum, T. B., Hahn, A., Meier, T., Davies, K. M. & Kühlbrandt, W. Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows. Proc. Natl Acad. Sci. USA 116, 4250–4255 (2019).

Cabezón, E., Arechaga, I., Butler, P. J. G. & Walker, J. E. Dimerization of bovine F1-ATPase by binding the inhibitor protein, IF1. J. Biol. Chem. 275, 28353–28355 (2000).

Gu, J. et al. Cryo-EM structure of the mammalian ATP synthase tetramer bound with inhibitory protein IF1. Science 364, 1068–1075 (2019).

Zou, H., Li, Y., Liu, X. & Wang, X. An APAf-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 274, 11549–11556 (1999).

Haworth, R. A. & Hunter, D. R. The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site. Arch. Biochem. Biophys. 195, 460–467 (1979).

Schinzel, A. C. et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl Acad. Sci. USA 102, 12005–12010 (2005).

Mnatsakanyan, N. et al. A mitochondrial megachannel resides in monomeric F1FO ATP synthase. Nat. Commun. 10, 1–11 (2019).

Davies, K. M., Blum, T. B. & Kühlbrandt, W. Conserved in situ arrangement of complex I and III2 in mitochondrial respiratory chain supercomplexes of mammals, yeast, and plants. Proc. Natl Acad. Sci. USA 115, 3024–3029 (2018). In situ structural study of supercomplex arrangement from mitochondria of different species.

Sousa, J. S., Mills, D. J., Vonck, J. & Kühlbrandt, W. Functional asymmetry and electron flow in the bovine respirasome. eLife 5, e21290 (2016).

Althoff, T., Mills, D. J., Popot, J.-L. & Kühlbrandt, W. Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1. EMBO J. 30, 4652–4664 (2011).

Maranzana, E., Barbero, G., Falasca, A. I., Lenaz, G. & Genova, M. L. Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid. Redox Signal. 19, 1469–1480 (2013).

Lopez-Fabuel, I. et al. Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Proc. Natl Acad. Sci. USA 113, 13063–13068 (2016).

Quinlan, C. L., Perevoshchikova, I. V., Hey-Mogensen, M., Orr, A. L. & Brand, M. D. Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biol. 1, 304–312 (2013).

Hou, T. et al. NDUFAB1 confers cardio-protection by enhancing mitochondrial bioenergetics through coordination of respiratory complex and supercomplex assembly. Cell Res. 29, 754–766 (2019).

Wang, G., Popovic, B., Tao, J. & Jiang, A. Overexpression of COX7RP promotes tumor growth and metastasis by inducing ROS production in hepatocellular carcinoma cells. Am. J. Cancer Res. 10, 1366–1383 (2020).

Ikeda, K. et al. Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance. Nat. Commun. 10, 1–15 (2019).

Blanchi, C., Genova, M. L., Castelli, G. P. & Lenaz, G. The mitochondrial respiratory chain is partially organized in a supercomplex assembly: hinetic evidence using flux control analysis. J. Biol. Chem. 279, 36562–36569 (2004).

Lapuente-Brun, E. et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science 340, 1567–1570 (2013). Biochemical characterization of the respiratory supercomplexes, proposing the existence of separate quinone pools.

Fedor, J. G. & Hirst, J. Mitochondrial supercomplexes do not enhance catalysis by quinone channeling. Cell Metab. 28, 525–531.e4 (2018). Biochemical characterization of the respiratory supercomplexes, disproving the existence of separate quinone pools.

Lobo-Jarne, T. & Ugalde, C. Respiratory chain supercomplexes: structures, function and biogenesis. Semin. Cell Dev. Biol. 76, 179–190 (2018).

Cogliati, S. et al. Mechanism of super-assembly of respiratory complexes III and IV. Nature 539, 579–582 (2016).

Sun, D., Li, B., Qiu, R., Fang, H. & Lyu, J. Cell type-specific modulation of respiratory chain supercomplex organization. Int. J. Mol. Sci. 17, 926 (2016).

Javadov, S., Jang, S., Chapa-Dubocq, X. R., Khuchua, Z. & Camara, A. K. Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role. J. Mol. Med. 99, 57–73 (2021).

Moreno-Lastres, D. et al. Mitochondrial complex I plays an essential role in human respirasome assembly. Cell Metab. 15, 324–335 (2012).

Acín-Pérez, R., Fernández-Silva, P., Peleato, M. L., Pérez-Martos, A. & Enriquez, J. A. Respiratory active mitochondrial supercomplexes. Mol. Cell 32, 529–539 (2008).

Fang, H. et al. A membrane arm of mitochondrial complex I sufficient to promote respirasome formation. Cell Rep. 35, 108963 (2021).

Novack, G. V., Galeano, P., Castaño, E. M. & Morelli, L. Mitochondrial supercomplexes: physiological organization and dysregulation in age-related neurodegenerative disorders. Front. Endocrinol. 11, 600 (2020).

Ikeda, K., Shiba, S., Horie-Inoue, K., Shimokata, K. & Inoue, S. A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle. Nat. Commun. 4, 1–9 (2013).

García-Poyatos, C. et al. Scaf1 promotes respiratory supercomplexes and metabolic efficiency in zebrafish. EMBO Rep. 21, e50287 (2020).

Shiba, S. et al. Deficiency of COX7RP, a mitochondrial supercomplex assembly promoting factor, lowers blood glucose level in mice. Sci. Rep. 7, 1–9 (2017).

Balsa, E. et al. ER and nutrient stress promote assembly of respiratory chain supercomplexes through the PERK-eIF2α Axis. Mol. Cell 74, 877–890.e6 (2019).

Pérez-Pérez, R. et al. COX7A2L is a mitochondrial complex III binding protein that stabilizes the III2+IV supercomplex without affecting respirasome formation. Cell Rep. 16, 2387–2398 (2016).

Lobo-Jarne, T. et al. Human COX7A2L regulates complex III biogenesis and promotes supercomplex organization remodeling without affecting mitochondrial bioenergetics. Cell Rep. 25, 1786–1799.e4 (2018).

Fernández-Vizarra, E. et al. SILAC-based complexome profiling dissects the structural organization of the human respiratory supercomplexes in SCAFI KO cells. Biochim. Biophys. Acta Bioenerg. 1862, 148414 (2021).

Mourier, A., Matic, S., Ruzzenente, B., Larsson, N. G. & Milenkovic, D. The respiratory chain supercomplex organization is independent of COX7A2L isoforms. Cell Metab. 20, 1069–1075 (2014).

Ameri, K. et al. HIGD1A regulates oxygen consumption, ROS production, and AMPK activity during glucose deprivation to modulate cell survival and tumor growth. Cell Rep. 10, 891–899 (2015).

Timón-Gómez, A., Bartley-Dier, E. L., Fontanesi, F. & Barrientos, A. HIGD-driven regulation of cytochrome c oxidase biogenesis and function. Cells 9, 2620 (2020).

Timón-Gómez, A., Garlich, J., Stuart, R. A., Ugalde, C. & Barrientos, A. Distinct roles of mitochondrial HIGD1A and HIGD2A in respiratory complex and supercomplex biogenesis. Cell Rep. 31, 107607 (2020).

Hock, D. H. et al. HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV. Mol. Cell. Proteom. 19, 1145–1160 (2020).

Hayashi, T. et al. DJ-1 binds to mitochondrial complex I and maintains its activity. Biochem. Biophys. Res. Commun. 390, 667–672 (2009).

Agip, A. N. A. et al. Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states. Nat. Struct. Mol. Biol. 25, 548–556 (2018).

Balsa, E. et al. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 16, 378–386 (2012).

Pitceathly, R. D. S. et al. NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. Cell Rep. 3, 1795–1805 (2013).

Berndtsson, J. et al. Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance. EMBO Rep. 21, e51015 (2020).

Blaza, J. N., Serreli, R., Jones, A. J. Y., Mohammed, K. & Hirst, J. Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes. Proc. Natl Acad. Sci. USA 111, 15735–15740 (2014).

Hackenbrock, C. R. Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. J. Cell Biol. 30, 269–297 (1966).

Scorrano, L. et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell 2, 55–67 (2002).

Cogliati, S. et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155, 160–171 (2013).

Barth, P. G. et al. An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. J. Neurol. Sci. 62, 327–355 (1983).

Xu, Y. et al. Loss of protein association causes cardiolipin degradation in Barth syndrome. Nat. Chem. Biol. 12, 641–647 (2016).

Hirst, J. Open questions: respiratory chain supercomplexes-why are they there and what do they do? BMC Biol. 16, 111 (2018).

Dudkina, N. V., Kouřil, R., Peters, K., Braun, H. P. & Boekema, E. J. Structure and function of mitochondrial supercomplexes. Biochim. Biophys. Acta Bioenerg. 1797, 664–670 (2010).

Chaban, Y., Boekema, E. J. & Dudkina, N. V. Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation. Biochim. Biophys. Acta Bioenerg. 1837, 418–426 (2014).

Bouvette, J. et al. Beam image-shift accelerated data acquisition for near-atomic resolution single-particle cryo-electron tomography. Nat. Commun. 12, 1957 (2021).

Yang, G. et al. Atp23p and Atp10p coordinate to regulate the assembly of yeast mitochondrial ATP synthase. FASEB J. 35, e21538 (2021).

De Grassi, A., Lanave, C. & Saccone, C. Evolution of ATP synthase subunit c and cytochrome c gene families in selected metazoan classes. Gene 371, 224–233 (2006).

Küster, U., Bohnensack, R. & Kunz, W. Control of oxidative phosphorylation by the extramitochondrial ATP/ADP ratio. BBA Bioenerg. 440, 391–402 (1976).

Meyrat, A. & von Ballmoos, C. ATP synthesis at physiological nucleotide concentrations. Sci. Rep. 9, 1–10 (2019).

Williams, G. I. Respiratory enzymes in oxidative phosphorylation III. The steady state. J. Biol. Chem. 217, 409–427 (1955).

Wikström, M. & Springett, R. Thermodynamic efficiency, reversibility, and degree of coupling in energy conservation by the mitochondrial respiratory chain. Commun. Biol. 3, 1–9 (2020).

Nicholls, D. G. The physiological regulation of uncoupling proteins. Biochim. Biophys. Acta Bioenerg. 1757, 459–466 (2006).

Wang, W. & Seale, P. Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17, 691–702 (2016).

Kory, N. et al. MCART1/SLC25A51 is required for mitochondrial NAD transport. Sci. Adv. 6, eabe5310 (2020).

Luongo, T. S. et al. SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature 588, 174–179 (2020).

Girardi, E. et al. Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import. Nat. Commun. 11, 1–9 (2020).

Ouyang, Y., Bott, A. J. & Rutter, J. Maestro of the SereNADe: SLC25A51 orchestrates mitochondrial NAD+. Trends Biochem. Sci. 46, 348–350 (2021).

Davila, A. et al. Nicotinamide adenine dinucleotide is transported into mammalian mitochondria. eLife 7, e33246 (2018).

Mills, E. L. et al. Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 560, 102–106 (2018).

Darvey, I. G. What factors are responsible for the greater yield of ATP per carbon atom when fatty acids are completely oxidised to CO2 and water compared with glucose? Biochem. Mol. Biol. Educ. 27, 209–210 (1999).

Rabinowitz, J. D. & Enerbäck, S. Lactate: the ugly duckling of energy metabolism. Nat. Metab. 2, 566–571 (2020).

Brand, M. D. The efficiency and plasticity of mitochondrial energy transduction. Biochem. Soc. Trans. 33, 897–904 (2005).

Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

DeBerardinis, R. J. & Chandel, N. S. We need to talk about the Warburg effect. Nat. Metab. 2, 127–129 (2020).

Bennett, N. K. et al. Defining the ATPome reveals cross-optimization of metabolic pathways. Nat. Commun. 11, 1–16 (2020).

Wilson, D. F., Rumsey, W. L., Green, T. J. & Vanderkooi, J. M. The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J. Biol. Chem. 263, 2712–2718 (1988).

Lee, P., Chandel, N. S. & Simon, M. C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21, 268–283 (2020).

Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Primers 2, 16081 (2016).

McFarland, R. & Turnbull, D. M. Batteries not included: diagnosis and management of mitochondrial disease. J. Intern. Med. 265, 210–228 (2009).

Smeitink, J. A., Zeviani, M., Turnbull, D. M. & Jacobs, H. T. Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metab. 3, 9–13 (2006).

Ghezzi, D. & Zeviani, M. Human diseases associated with defects in assembly of OXPHOS complexes. Essays Biochem. 62, 271–286 (2018).

Frazier, A. E., Thorburn, D. R. & Compton, A. G. Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology. J. Biol. Chem. 294, 5386–5395 (2019).

Vafai, S. B. & Mootha, V. K. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374–383 (2012).

Schubert, M. B. & Vilarinho, L. Molecular basis of Leigh syndrome: a current look. Orphanet J. Rare Dis. 15, 1–14 (2020).

El-Hattab, A. W., Adesina, A. M., Jones, J. & Scaglia, F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol. Genet. Metab. 116, 4–12 (2015).

Finsterer, J. & Zarrouk-Mahjoub, S. Leber’s hereditary optic neuropathy is multiorgan not mono-organ. Clin. Ophthalmol. 10, 2187–2190 (2016).

Fiedorczuk, K. & Sazanov, L. A. Mammalian mitochondrial complex I structure and disease-causing mutations. Trends Cell Biol. 28, 835–867 (2018).

Dalla Pozza, E. et al. Regulation of succinate dehydrogenase and role of succinate in cancer. Semin. Cell Dev.Biol. 98, 4–14 (2020).

Moosavi, B., Zhu, X. L., Yang, W. C. & Yang, G. F. Molecular pathogenesis of tumorigenesis caused by succinate dehydrogenase defect. Eur. J. Cell Biol. 99, 151057 (2020).

Ryan, D. G. et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat. Metab. 1, 16–33 (2019).

Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470 (2016).

Bonello, S. et al. Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site. Arterioscler. Thromb. Vasc. Biol. 27, 755–761 (2007).

Weinberg, S. E. et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565, 495–499 (2019).

Fazakerley, D. J. et al. Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance. eLife 7, e32111 (2018).

Alcázar-Fabra, M., Navas, P. & Brea-Calvo, G. Coenzyme Q biosynthesis and its role in the respiratory chain structure. Biochim. Biophys. Acta. 1857, 1073–1078 (2016).

Desbats, M. A., Lunardi, G., Doimo, M., Trevisson, E. & Salviati, L. Genetic bases and clinical manifestations of coenzyme Q10 (CoQ10) deficiency. J. Inherit. Metab. Dis. 38, 145–156 (2015).

Martínez-Reyes, I. et al. Mitochondrial ubiquinol oxidation is necessary for tumour growth. Nature 585, 288–292 (2020).

Liu, X., Kim, C. N., Yang, J., Jemmerson, R. & Wang, X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147–157 (1996).

Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

Li, K. et al. Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101, 389–399 (2000).

Sazanov, L. A. A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat. Rev. Mol. Cell Biol. 16, 375–388 (2015).

Wirth, C., Brandt, U., Hunte, C. & Zickermann, V. Structure and function of mitochondrial complex I. Biochim. Biophys. Acta 1857, 902–914 (2016).

Parey, K. et al. High-resolution cryo-EM structures of respiratory complex I: mechanism, assembly, and disease. Sci. Adv. 5, eaax9484 (2019).