Mitochondrial fusion & function in CMT 2A patient fibroblasts with mitofusin 2 m

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Exp Neurol. 2008 Jan 26

Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A

patient fibroblasts with mitofusin 2 mutations.

Amiott EA, Lott P, Soto J, Kang PB, McCaffery JM, Dimauro S, Abel ED,

Flanigan KM, Lawson VH, Shaw JM.

Department of Biochemistry, University of Utah School of Medicine,

Salt Lake City, UT, 84112, USA.

Charcot-Marie-Tooth Type 2A is a dominantly inherited peripheral

neuropathy characterized by axonal degeneration of sensory and motor

nerves. The disease is caused by mutations in the mitochondrial

fusion gene MFN2. Mfn2 is an integral outer mitochondrial membrane

protein composed o

f a large GTPase domain and two heptad repeat (HR) domains that face

the cytoplasm. Mitochondrial membrane fusion and division are

balanced processes that are necessary to maintain tubular

mitochondrial morphology, respiratory function, and uniform

distribution of the organelle throughout the cell.

We have utilized primary fibroblasts from CMT2A patients to survey

mitochondrial phenotypes associated with heterozygous MFN2 alleles

expressed at physiological levels. Our results indicate that, in

fibroblasts, mitofusin expression, mitochondrial morphology,

ultrastructure, mtDNA content, and respiratory capacity are not

affected by the presence of mutant Mfn2 protein.

Consistent with a lack of mitochondrial dysfunction, we also show

that mitochondrial fusion occurs efficiently in CMT2A patient-derived

fibroblasts.

Our observations are in agreement with the neuronal specificity of

the disease and are consistent with a recent finding that

mitochondrial fusion can be maintained in cells that express mutant

Mfn2 protein due to complementation by a second mitofusin, Mfn1. We

discuss our results and those of others in terms of a comprehensive

model for the mechanism(s) by which mutations in MFN2 may lead to

CMT2A disease.