Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

Emilie Hangen, Olivier Féraud, Sylvie Lachkar, Haiwei Mou, Nunzianna Doti, Gian Maria Fimia, Ngoc vy Lam, Changlian Zhu, Isabelle Godin, Kevin Muller, Afroditi Chatzi, Esther Nuebel, Fabiola Ciccosanti, Stéphane Flamant, Paule Bénit, Jean Luc Perfettini, Allan Sauvat, Annelise Bennaceur-Griscelli, Karine Ser-Le Roux, Patrick GoninKostas Tokatlidis, Pierre Rustin, Mauro Piacentini, Menotti Ruvo, Klas Blomgren, Guido Kroemer, Nazanine Modjtahedi

Research output: Contribution to journalArticlepeer-review


Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.

Original languageEnglish
Pages (from-to)1001-1014
Number of pages14
JournalMolecular Cell
Issue number6
Publication statusPublished - Jun 18 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)


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