2. Academic Validation
  3. Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

  • Mol Cell. 2015 Jun 18;58(6):1001-14. doi: 10.1016/j.molcel.2015.04.020.
Emilie Hangen 1,  Olivier Féraud 2,  Sylvie Lachkar 1,  Haiwei Mou 1,  Nunzianna Doti 3,  Gian Maria Fimia 4,  Ngoc-Vy Lam 1,  Changlian Zhu 5,  Isabelle Godin 6,  Kevin Muller 1,  Afroditi Chatzi 7,  Esther Nuebel 7,  Fabiola Ciccosanti 8,  Stéphane Flamant 9,  Paule Bénit 10,  Jean-Luc Perfettini 11,  Allan Sauvat 12,  Annelise Bennaceur-Griscelli 13,  Karine Ser-Le Roux 14,  Patrick Gonin 14,  Kostas Tokatlidis 7,  Pierre Rustin 10,  Mauro Piacentini 15,  Menotti Ruvo 3,  Klas Blomgren 16,  Guido Kroemer 17,  Nazanine Modjtahedi 18
Affiliations

Affiliations

  • 1 Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; INSERM, UMRS 1138, 75006 Paris, France; Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006 Paris, France; Université Pierre et Marie Curie, 75006 Paris, France.
  • 2 Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; INSERM U935, 94805 Villejuif, France; ESTeam Paris Sud, Stem Cell Core Facility, Institut André Lwoff, 94800 Villejuif, France.
  • 3 Istituto di Biostrutture e Bioimmagini, CNR, 80134 Napoli, Italy.
  • 4 Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS "L. Spallanzani," 00149 Rome, Italy; Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce 73100, Italy.
  • 5 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, 40530 Gothenburg, Sweden.
  • 6 Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; INSERM U1009, 94805 Villejuif, France.
  • 7 Institute of Molecular Cell and Systems Biology, University of Glasgow, G12 8QQ Glasgow, UK; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion Crete 70013, Greece.
  • 8 Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS "L. Spallanzani," 00149 Rome, Italy.
  • 9 Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; INSERM U935, 94805 Villejuif, France.
  • 10 INSERM UMR1141, Hôpital Robert Debré, 75019 Paris, France; Faculté de Médecine Denis Diderot, Université Paris 7, 75013 Paris, France.
  • 11 Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; Cell Death and Aging Team, Gustave Roussy, 94805 Villejuif, France; INSERM U1030, Gustave Roussy, 94805 Villejuif, France.
  • 12 Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; INSERM, UMRS 1138, 75006 Paris, France; Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France.
  • 13 Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; INSERM U935, 94805 Villejuif, France; ESTeam Paris Sud, Stem Cell Core Facility, Institut André Lwoff, 94800 Villejuif, France; Laboratoire d'Hématologie, Hôpital Paul Brousse AP-HP, 94800 Villejuif, France.
  • 14 Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; Animal and Veterinary Resources, 94805 Villejuif, France.
  • 15 Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS "L. Spallanzani," 00149 Rome, Italy; Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy.
  • 16 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, 40530 Gothenburg, Sweden; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, 171 76 Stockholm, Sweden.
  • 17 Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; INSERM, UMRS 1138, 75006 Paris, France; Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006 Paris, France; Université Pierre et Marie Curie, 75006 Paris, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France. Electronic address: [email protected].
  • 18 Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; INSERM, UMRS 1138, 75006 Paris, France; Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006 Paris, France; Université Pierre et Marie Curie, 75006 Paris, France. Electronic address: [email protected].
PMID: 26004228 DOI: 10.1016/j.molcel.2015.04.020
Abstract

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.

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