title: Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis.
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.
authors.affiliation: 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.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hangen
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Féraud
authors.affiliation: 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.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lachkar
authors.affiliation: 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.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Mou
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, 80134 Napoli, Italy.
authors.forename: Nunzianna
authors.initials: N
authors.lastname: Doti
authors.affiliation: 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.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: 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.
authors.forename: Ngoc-Vy
authors.initials: NV
authors.lastname: Lam
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, 40530 Gothenburg, Sweden.
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; INSERM U1009, 94805 Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Godin
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Muller
authors.affiliation: 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.
authors.forename: Afroditi
authors.initials: A
authors.lastname: Chatzi
authors.affiliation: 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Nuebel
authors.affiliation: Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS "L. Spallanzani," 00149 Rome, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Ciccosanti
authors.affiliation: Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; INSERM U935, 94805 Villejuif, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Flamant
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, 75019 Paris, France; Faculté de Médecine Denis Diderot, Université Paris 7, 75013 Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.affiliation: 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.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.affiliation: 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.
authors.forename: Allan
authors.initials: A
authors.lastname: Sauvat
authors.affiliation: 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.
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.affiliation: Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; Animal and Veterinary Resources, 94805 Villejuif, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Ser-Le Roux
authors.affiliation: Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Université Paris Sud/Paris XI, 94270 Kremlin Bicêtre, France; Animal and Veterinary Resources, 94805 Villejuif, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonin
authors.affiliation: 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.
authors.forename: Kostas
authors.initials: K
authors.lastname: Tokatlidis
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, 75019 Paris, France; Faculté de Médecine Denis Diderot, Université Paris 7, 75013 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: 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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, 80134 Napoli, Italy.
authors.forename: Menotti
authors.initials: M
authors.lastname: Ruvo
authors.affiliation: 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.
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.affiliation: 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: kroemer@orange.fr.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: 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: nazanine.modjtahedi@gustaveroussy.fr.
authors.forename: Nazanine
authors.initials: N
authors.lastname: Modjtahedi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004579:Electron Transport / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference; D013997:Time Factors
chemical_list: D051033:Apoptosis Inducing Factor; C507282:CHCHD4 protein, human; D045222:Electron Transport Chain Complex Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins