CMT Type 2 : Altered Axonal Mitochondrial Transport in the Pathogenesis of Char

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The Journal of Neuroscience, January 10, 2007, 27(2):422-430;

Altered Axonal Mitochondrial Transport in the Pathogenesis of

Charcot-Marie-Tooth Disease from Mitofusin 2 Mutations

H. Baloh, E. Schmidt, Alan Pestronk, and

Milbrandt

Departments of Neurology and Pathology and Hope Center for

Neurological Diseases, Washington University School of Medicine, St.

Louis, Missouri 63110

Correspondence should be addressed to H. Baloh, Department of

Neurology, Washington University School of Medicine, P.O. Box 8111,

660 South Euclid Avenue, St. Louis, MO 63110.

Mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) are

the most commonly identified cause of Charcot-Marie-Tooth type 2

(CMT2), a dominantly inherited disease characterized by degeneration

of peripheral sensory and motor axons. However, the mechanism by

which mutations in this ubiquitously expressed mitochondrial fusion

protein lead to neuropathy has not yet been elucidated. To explore

how MFN2 mutations lead to degeneration of peripheral axons, we

expressed neuropathy-associated forms of MFN2 in cultured dorsal

root ganglion neurons, cells preferentially affected in CMT2.

Disease-associated MFN2 mutant proteins induced abnormal clustering

of small fragmented mitochondria in both neuronal cell bodies and

proximal axons. Interestingly, transport of mitochondria in axons

was significantly impaired in neurons expressing disease-mutated

forms of MFN2. The diminished axonal mitochondrial transport was not

attributable to diminished ATP levels in the neurons, and oxidative

respiration was normal in mutant MFN2-expressing cells.

Additionally, mitochondrial oxidative enzyme activity was normal in

muscle mitochondria from a CMT2 patient with an MFN2 mutation,

further supporting that abnormal mitochondrial transport in neurons

is independent from an energy production defect. This abnormal

mitochondrial trafficking provides a likely explanation for the

selective susceptibility of the longest peripheral axons to MFN2

mutations, in which proper localization of mitochondria is critical

for axonal and synaptic function.

Key words: axon; axonal transport (axoplasmic transport); genetics;

mitochondria; neuropathy; trafficking