title: Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4.
abstract: Hypomorphic mutation of apoptosis-inducing factor (AIF) in the whole body or organ-specific knockout of AIF compromises the activity of respiratory chain complexes I and IV, as it confers resistance to obesity and diabetes induced by high-fat diet. The mitochondrial defect induced by AIF deficiency can be explained by reduced AIF-dependent mitochondrial import of CHCHD4, which in turn is required for optimal import and assembly of respiratory chain complexes. Here we show that, as compared to wild type control littermates, mice with a heterozygous knockout of CHCHD4 exhibit reduced weight gain when fed with a Western style high-fat diet. This finding suggests widespread metabolic epistasis among AIF and CHCHD4. Targeting either of these proteins or their functional interaction might constitute a novel strategy to combat obesity.
authors.affiliation: a Equipe 11 labellisée Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris , France.
authors.forename: Nazanine
authors.initials: N
authors.lastname: Modjtahedi
authors.forename: Emilie
authors.initials: E
authors.lastname: Hangen
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonin
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000379:methods; D004843:Epistasis, Genetic / Q000502:physiology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins
chemical_list: D051033:Apoptosis Inducing Factor; C507282:CHCHD4 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins
keywords: Apoptosis; diabetes; metabolism; obesity; programmed cell death