Respiratory supercomplexes act as a platform for complex III-mediated maturation of human mitochondrial complexes I and IV

Margherita Protasoni, Rafael Pérez-Pérez, Teresa Lobo-Jarne, Michael E. Harbour, Shujing Ding, Ana Peñas, Francisca Diaz, Carlos T. Moraes, Ian M. Fearnley, Massimo Zeviani, Cristina Ugalde, Erika Fernández-Vizarra

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50 Scopus citations


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.

Original languageEnglish (US)
Article numbere102817
JournalEMBO Journal
Issue number3
StatePublished - Feb 3 2020


  • complex I
  • complex III
  • cytochrome b mutation
  • mitochondrial respiratory chain assembly
  • supercomplexes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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