@article{574ac8cf38e64c54ac0bc5265920adfe,
title = "Respiratory supercomplexes act as a platform for complex III-mediated maturation of human mitochondrial complexes I and IV",
abstract = "Mitochondrial respiratory chain (MRC) enzymes associate in supercomplexes (SCs) that are structurally interdependent. This may explain why defects in a single component often produce combined enzyme deficiencies in patients. A case in point is the alleged destabilization of complex I in the absence of complex III. To clarify the structural and functional relationships between complexes, we have used comprehensive proteomic, functional, and biogenetical approaches to analyze a MT-CYB-deficient human cell line. We show that the absence of complex III blocks complex I biogenesis by preventing the incorporation of the NADH module rather than decreasing its stability. In addition, complex IV subunits appeared sequestered within complex III subassemblies, leading to defective complex IV assembly as well. Therefore, we propose that complex III is central for MRC maturation and SC formation. Our results challenge the notion that SC biogenesis requires the pre-formation of fully assembled individual complexes. In contrast, they support a cooperative-assembly model in which the main role of complex III in SCs is to provide a structural and functional platform for the completion of overall MRC biogenesis.",
keywords = "complex I, complex III, cytochrome b mutation, mitochondrial respiratory chain assembly, supercomplexes",
author = "Margherita Protasoni and Rafael P{\'e}rez-P{\'e}rez and Teresa Lobo-Jarne and Harbour, {Michael E.} and Shujing Ding and Ana Pe{\~n}as and Francisca Diaz and Moraes, {Carlos T.} and Fearnley, {Ian M.} and Massimo Zeviani and Cristina Ugalde and Erika Fern{\'a}ndez-Vizarra",
note = "Funding Information: We are grateful to Antonio Barrientos (University of Miami, USA) for critically revising the manuscript and to Justin G. Fedor (Mitochondrial Biology Unit, Cambridge, UK), Leonid A. Sazanov (IST Austria, Klosterneuburg, Austria), and James A. Letts (University of California, Davis, USA) for scientific discussions. We also thank Irenaeus F. de Coo (Erasmus University, The Netherlands) for the original patient fibroblasts used to produce cybrids and Ester Perales-Clemente and M. Pilar Bayona-Bafaluy (University of Zaragoza, Spain) for providing the PuroR and HygroR lentiviral expression vectors. Our research was supported by the Core Grant from the Medical Research Council (Grant MC_UU_00015/5), ERC Advanced Grant FP7-3222424 and NRJ-Institut de France Grant (to M.Z.), Association Fran?aise contre les Myopathies (AFM) grant 16086 (to E.F-V.), Instituto de Salud Carlos III-MINECO/European ERDF-ESF grant PI17-00048, Comunidad Aut?noma de Madrid/ERDF-ESF grant P2018/BAA-4403, and NIH-RO1 grant GM105781 (to C.U.). Funding Information: We are grateful to Antonio Barrientos (University of Miami, USA) for critically revising the manuscript and to Justin G. Fedor (Mitochondrial Biology Unit, Cambridge, UK), Leonid A. Sazanov (IST Austria, Klosterneuburg, Austria), and James A. Letts (University of California, Davis, USA) for scientific discussions. We also thank Irenaeus F. de Coo (Erasmus University, The Netherlands) for the original patient fibroblasts used to produce cybrids and Ester Perales‐Clemente and M. Pilar Bayona‐Bafaluy (University of Zaragoza, Spain) for providing the Puro and Hygro lentiviral expression vectors. Our research was supported by the Core Grant from the Medical Research Council (Grant MC_UU_00015/5), ERC Advanced Grant FP7‐3222424 and NRJ‐Institut de France Grant (to M.Z.), Association Fran{\c c}aise contre les Myopathies (AFM) grant 16086 (to E.F‐V.), Instituto de Salud Carlos III‐MINECO/European ERDF‐ESF grant PI17‐00048, Comunidad Aut{\'o}noma de Madrid/ERDF‐ESF grant P2018/BAA‐4403, and NIH‐RO1 grant GM105781 (to C.U.). R R Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = feb,
day = "3",
doi = "10.15252/embj.2019102817",
language = "English (US)",
volume = "39",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "3",
}