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Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV.

Vercellino I, Sazanov LA
Nature 598 364-367 (2021)
Related entries: 7o37, 7o3c, 7o3h

Cited: 23 times
EuropePMC logo PMID: 34616041

Abstract

The enzymes of the mitochondrial electron transport chain are key players of cell metabolism. Despite being active when isolated, in vivo they associate into supercomplexes1, whose precise role is debated. Supercomplexes CIII2CIV1-2 (refs. 2,3), CICIII2 (ref. 4) and CICIII2CIV (respirasome)5-10 exist in mammals, but in contrast to CICIII2 and the respirasome, to date the only known eukaryotic structures of CIII2CIV1-2 come from Saccharomyces cerevisiae11,12 and plants13, which have different organization. Here we present the first, to our knowledge, structures of mammalian (mouse and ovine) CIII2CIV and its assembly intermediates, in different conformations. We describe the assembly of CIII2CIV from the CIII2 precursor to the final CIII2CIV conformation, driven by the insertion of the N terminus of the assembly factor SCAF1 (ref. 14) deep into CIII2, while its C terminus is integrated into CIV. Our structures (which include CICIII2 and the respirasome) also confirm that SCAF1 is exclusively required for the assembly of CIII2CIV and has no role in the assembly of the respirasome. We show that CIII2 is asymmetric due to the presence of only one copy of subunit 9, which straddles both monomers and prevents the attachment of a second copy of SCAF1 to CIII2, explaining the presence of one copy of CIV in CIII2CIV in mammals. Finally, we show that CIII2 and CIV gain catalytic advantage when assembled into the supercomplex and propose a role for CIII2CIV in fine tuning the efficiency of electron transfer in the electron transport chain.

Reviews citing this publication (10)

  1. Metabolic regulation of endothelial senescence. Le NT. Front Cardiovasc Med 10 1232681 (2023)
  2. Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention. van de Wal MAE, Adjobo-Hermans MJW, Keijer J, Schirris TJJ, Homberg JR, Wieckowski MR, Grefte S, van Schothorst EM, van Karnebeek C, Quintana A, Koopman WJH. Brain 145 45-63 (2022)
  3. Regulation and functional role of the electron transport chain supercomplexes. Cogliati S, Cabrera-Alarcón JL, Enriquez JA. Biochem Soc Trans 49 2655-2668 (2021)
  4. The biogenesis and regulation of the plant oxidative phosphorylation system. Ghifari AS, Saha S, Murcha MW. Plant Physiol 192 728-747 (2023)
  5. The functional significance of mitochondrial respiratory chain supercomplexes. Kohler A, Barrientos A, Fontanesi F, Ott M. EMBO Rep 24 e57092 (2023)
  6. An evolving view of complex II-noncanonical complexes, megacomplexes, respiration, signaling, and beyond. Iverson TM, Singh PK, Cecchini G. J Biol Chem 299 104761 (2023)
  7. Mechanisms of mitochondrial respiratory adaptation. Bennett CF, Latorre-Muro P, Puigserver P. Nat Rev Mol Cell Biol 23 817-835 (2022)
  8. Mitochondrial Oxidative Phosphorylation in Viral Infections. Purandare N, Ghosalkar E, Grossman LI, Aras S. Viruses 15 2380 (2023)
  9. Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function. Guan S, Zhao L, Peng R. Int J Mol Sci 23 13880 (2022)
  10. Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights. Jain A, Casanova D, Padilla AV, Paniagua Bojorges A, Kotla S, Ko KA, Samanthapudi VSK, Chau K, Nguyen MTH, Wen J, Hernandez Gonzalez SL, Rodgers SP, Olmsted-Davis EA, Hamilton DJ, Reyes-Gibby C, Yeung SJ, Cooke JP, Herrmann J, Chini EN, Xu X, Yusuf SW, Yoshimoto M, Lorenzi PL, Hobbs B, Krishnan S, Koutroumpakis E, Palaskas NL, Wang G, Deswal A, Lin SH, Abe JI, Le NT. Front Cardiovasc Med 10 1212174 (2023)

Articles citing this publication (13)

  1. Resting mitochondrial complex I from Drosophila melanogaster adopts a helix-locked state. Padavannil A, Murari A, Rhooms SK, Owusu-Ansah E, Letts JA. Elife 12 e84415 (2023)
  2. Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes. Brischigliaro M, Cabrera-Orefice A, Arnold S, Viscomi C, Zeviani M, Fernández-Vizarra E. Elife 12 RP88084 (2023)
  3. A FRET-based respirasome assembly screen identifies spleen tyrosine kinase as a target to improve muscle mitochondrial respiration and exercise performance in mice. Kobayashi A, Azuma K, Takeiwa T, Kitami T, Horie K, Ikeda K, Inoue S. Nat Commun 14 312 (2023)
  4. COX7A2L genetic variants determine cardiorespiratory fitness in mice and human. Benegiamo G, Bou Sleiman M, Wohlwend M, Rodríguez-López S, Goeminne LJE, Laurila PP, Klevjer M, Salonen MK, Lahti J, Jha P, Cogliati S, Enriquez JA, Brumpton BM, Bye A, Eriksson JG, Auwerx J. Nat Metab 4 1336-1351 (2022)
  5. Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV. Corey RA, Harrison N, Stansfeld PJ, Sansom MSP, Duncan AL. Chem Sci 13 13489-13498 (2022)
  6. Cryo-EM structure of the four-subunit Rhodobacter sphaeroides cytochrome bc1 complex in styrene maleic acid nanodiscs. Swainsbury DJK, Hawkings FR, Martin EC, Musiał S, Salisbury JH, Jackson PJ, Farmer DA, Johnson MP, Siebert CA, Hitchcock A, Hunter CN. Proc Natl Acad Sci U S A 120 e2217922120 (2023)
  7. Electron transport system supercomplexes affect reactive-oxygen species production and respiration in both a hibernator (Ictidomys tridecemlineatus) and a nonhibernator (Rattus norvegicus). Hutchinson AJ, Duffy BM, Staples JF. J Comp Physiol B (2023)
  8. Structural Analysis of Mitochondria in Cardiomyocytes: Insights into Bioenergetics and Membrane Remodeling. Adams RA, Liu Z, Hsieh C, Marko M, Lederer WJ, Jafri MS, Mannella C. Curr Issues Mol Biol 45 6097-6115 (2023)
  9. Structural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex. Hryc CF, Mallampalli VKPS, Bovshik EI, Azinas S, Fan G, Serysheva II, Sparagna GC, Baker ML, Mileykovskaya E, Dowhan W. Nat Commun 14 2783 (2023)
  10. Structures of Tetrahymena's respiratory chain reveal the diversity of eukaryotic core metabolism. Zhou L, Maldonado M, Padavannil A, Guo F, Letts JA. Science 376 831-839 (2022)
  11. Structures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae. Han F, Hu Y, Wu M, He Z, Tian H, Zhou L. Nat Commun 14 2542 (2023)
  12. The coupling mechanism of mammalian mitochondrial complex I. Gu J, Liu T, Guo R, Zhang L, Yang M. Nat Struct Mol Biol 29 172-182 (2022)
  13. Unbiased Phosphoproteome Mining Reveals New Functional Sites of Metabolite-Derived PTMs Involved in MASLD Development. Moltó E, Pintado C, Louzada RA, Bernal-Mizrachi E, Andrés A, Gallardo N, Bonzon-Kulichenko E. Int J Mol Sci 24 16172 (2023)


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