CMT 2A: Mitofusin 2 is necessary for transport of axonal mitochondria and inter

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J Neurosci. 2010 Mar 24;30(12):4232-40.

Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with

the miro/milton complex.

Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH.

Department of Neurology and Hope Center for Neurological Diseases, Washington

University School of Medicine, St. Louis, Missouri 63110.

Mitofusins (Mfn1 and Mfn2) are outer mitochondrial membrane proteins involved in

regulating mitochondrial dynamics. Mutations in Mfn2 cause Charcot-Marie-Tooth

disease (CMT) type 2A, an inherited disease characterized by degeneration of

long peripheral axons, but the nature of this tissue selectivity remains

unknown.

Here, we present evidence that Mfn2 is directly involved in and required for

axonal mitochondrial transport, distinct from its role in mitochondrial fusion.

Live imaging of neurons cultured from Mfn2 knock-out mice or neurons expressing

Mfn2 disease mutants shows that axonal mitochondria spend more time paused and

undergo slower anterograde and retrograde movements, indicating an alteration in

attachment to microtubule-based transport systems.

Furthermore, Mfn2 disruption altered mitochondrial movement selectively, leaving

transport of other organelles intact. Importantly, both Mfn1 and Mfn2 interact

with mammalian Miro (Miro1/Miro2) and Milton (OIP106/GRIF1) proteins, members of

the molecular complex that links mitochondria to kinesin motors. Knockdown of

Miro2 in cultured neurons produced transport deficits identical to loss of Mfn2,

indicating that both proteins must be present at the outer membrane to mediate

axonal mitochondrial transport.

In contrast, disruption of mitochondrial fusion via knockdown of the inner

mitochondrial membrane protein Opa1 had no effect on mitochondrial motility,

indicating that loss of fusion does not inherently alter mitochondrial

transport. These experiments identify a role for mitofusins in directly

regulating mitochondrial transport and offer important insight into the cell

type specificity and molecular mechanisms of axonal degeneration in CMT2A and

dominant optic atrophy.