Journal Article

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

Sara Pich, Daniel Bach, Paz Briones, Marc Liesa, Marta Camps, Xavier Testar, Manuel Palacín and Antonio Zorzano

in Human Molecular Genetics

Volume 14, issue 11, pages 1405-1415
Published in print June 2005 | ISSN: 0964-6906
Published online April 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi149
The Charcot–Marie–Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

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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.

Journal Article.  7485 words.  Illustrated.

Subjects: Genetics and Genomics

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