2A gene product, Mfn2,upregulates fuel oxidation through expression of OXPHOS..

[Guest guest]

Hum Mol Genet. 2005 Apr 13;

The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel

oxidation through expression of OXPHOS system.

Pich S, Bach D, Briones P, Liesa M, Camps M, Testar X, Palacin M,

Zorzano A.

Departament de Bioquimica i Biologia Molecular, Facultat de Biologia,

Universitat de Barcelona, and IRBB-PCB, Parc Cientific de Barcelona,

Barcelona, Spain.

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 over-expression 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.