title: The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system.
abstract: Mitofusin-2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells and mutations in the Mfn2 gene cause Charcot-Marie-Tooth neuropathy type 2A. Here, we show that Mfn2 loss-of-function inhibits pyruvate, glucose and fatty acid oxidation and reduces mitochondrial membrane potential, whereas Mfn2 gain-of-function increases glucose oxidation and mitochondrial membrane potential. As to the mechanisms involved, we have found that Mfn2 loss-of-function represses nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas Mfn2 overexpression induced the subunits of complexes I, IV and V. Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III and V. In addition, the effect of Mfn2 overexpression on mitochondrial metabolism was mimicked by a truncated Mfn2 mutant that is inactive as a mitochondrial fusion protein. Our results indicate that Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IRBB-PCB, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Pich
authors.forename: Daniel
authors.initials: D
authors.lastname: Bach
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.forename: Marta
authors.initials: M
authors.lastname: Camps
authors.forename: Xavier
authors.initials: X
authors.lastname: Testar
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
mesh_terms: D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism*; D017931:DNA Primers; D005227:Fatty Acids / Q000378:metabolism*; D020558:GTP Phosphohydrolases; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D019289:Pyruvic Acid / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D005227:Fatty Acids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019289:Pyruvic Acid; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; D005947:Glucose