Two independent respiratory chains adapt OXPHOS performance to glycolytic switch

Erika Fernández-Vizarra, Sandra López-Calcerrada, Ana Sierra-Magro, Rafael Pérez-Pérez, Luke E. Formosa, Daniella H. Hock, María Illescas, Ana Peñas, Michele Brischigliaro, Shujing Ding, Ian M. Fearnley, Charalampos Tzoulis, Robert D.S. Pitceathly, Joaquín Arenas, Miguel A. Martín, David A. Stroud, Massimo Zeviani, Michael T. Ryan, Cristina Ugalde

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20 Citations (Scopus)


The structural and functional organization of the mitochondrial respiratory chain (MRC) remains intensely debated. Here, we show the co-existence of two separate MRC organizations in human cells and postmitotic tissues, C-MRC and S-MRC, defined by the preferential expression of three COX7A subunit isoforms, COX7A1/2 and SCAFI (COX7A2L). COX7A isoforms promote the functional reorganization of distinct co-existing MRC structures to prevent metabolic exhaustion and MRC deficiency. Notably, prevalence of each MRC organization is reversibly regulated by the activation state of the pyruvate dehydrogenase complex (PDC). Under oxidative conditions, the C-MRC is bioenergetically more efficient, whereas the S-MRC preferentially maintains oxidative phosphorylation (OXPHOS) upon metabolic rewiring toward glycolysis. We show a link between the metabolic signatures converging at the PDC and the structural and functional organization of the MRC, challenging the widespread notion of the MRC as a single functional unit and concluding that its structural heterogeneity warrants optimal adaptation to metabolic function.

Original languageEnglish
Pages (from-to)1792-1808.e6
Number of pages24
JournalCell Metabolism
Issue number11
Publication statusPublished - 1 Nov 2022


  • bioenergetics
  • COX7A1–2
  • glycolysis
  • metabolic switch
  • mitochondria
  • oxidative metabolism
  • pyruvate dehydrogenase
  • respiratory chain organizations
  • respiratory supercomplexes

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