CMT 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXP

[Guest guest]

Hum Mol Genet. 2005 Jun 1;14(11):1405-15.

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.

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.