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We thank Dr. Erika Fernandez-Vizarra for critically reading the manuscript, and Prof. G. Manfredi and Prof. J.A. Enriquez for providing the mutant cybrids. Nano-LC/ESI-MS analyses were carried out at the Proteomics Facility UCM-FPCM/ProteoRed (Spain). Research was supported by Instituto de Salud Carlos III-MINECO/European FEDER Funds grants PI14-00209 and PI17-00048 (to CU) and PI18-00374 (to MAM), by Comunidad Autonoma de Madrid/ERDF-ESF grant P2018/BAA-4403 (to CU), by NIH-RO1 grants GM105781 (to AB and CU) and GM112179 (to AB), NIH-R35 grant GM118141 (to AB), MDA grant MDA-381828 (to AB), an AHA development grant 14SDG20040003 (to FF), by Bundesministerium fur Bildung und Forschung (BMBF 01GM1906D; mitoNET-Deutsches Netzwerk fur mitochondriale Erkrankungen), and by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 815, Project Z1 (to IW).

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Multiple pathways coordinate assembly of human mitochondrial complex IV and stabilization of respiratory supercomplexes

Publicat a:Embo Journal. 39 (14): e103912- - 2020-06-08 39(14), DOI: 10.15252/embj.2019103912

Autors: Lobo-Jarne, Teresa; Perez-Perez, Rafael; Fontanesi, Flavia; Timon-Gomez, Alba; Wittig, Ilka; Penas, Ana; Serrano-Lorenzo, Pablo; Garcia-Consuegra, Ines; Arenas, Joaquin; Martin, Miguel A; Barrientos, Antoni; Ugalde, Cristina

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Mitochondrial respiratory chain complexes I, III, and IV can associate into larger structures termed supercomplexes or respirasomes, thereby generating structural interdependences among the individual complexes yet to be understood. In patients, nonsense mutations in complex IV subunit genes cause severe encephalomyopathies randomly associated with pleiotropic complex I defects. Using complexome profiling and biochemical analyses, we have explored the structural rearrangements of the respiratory chain in human cell lines depleted of the catalytic complex IV subunit COX1 or COX2. In the absence of a functional complex IV holoenzyme, several supercomplex I+III2 species coexist, which differ in their content of COX subunits and COX7A2L/HIGD2A assembly factors. The incorporation of an atypical COX1-HIGD2A submodule attenuates supercomplex I+III2 turnover rate, indicating an unexpected molecular adaptation for supercomplexes stabilization that relies on the presence of COX1 independently of holo-complex IV formation. Our data set the basis for complex I structural dependence on complex IV, revealing the co-existence of alternative pathways for the biogenesis of "supercomplex-associated" versus individual complex IV, which could determine physiological adaptations under different stress and disease scenarios.

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