The Charcot–Marie–Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

• Published in: Human molecular genetics 2005-06, Vol.14 (11), p.1405-1415
• Main Authors: Pich, Sara, Bach, Daniel, Briones, Paz, Liesa, Marc, Camps, Marta, Testar, Xavier, Palacín, Manuel, Zorzano, Antonio
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; Charcot-Marie-Tooth Disease - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Primers; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glucose - metabolism; GTP Phosphohydrolases; Humans; Medical sciences; Membrane Potentials; Membrane Proteins - genetics; Membrane Proteins - physiology; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - physiology; Molecular and cellular biology; Neurology; Oxidation-Reduction; Oxidative Phosphorylation; Pyruvic Acid - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi149

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.