Mitofusin 2 Protects Cerebellar Granule Neurons against Injury-induced Cell Deat

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J. Biol. Chem., Vol. 282, Issue 33, 23788-23798, August 17, 2007

Mitofusin 2 Protects Cerebellar Granule Neurons against Injury-

induced Cell Death

Arezu Jahani-Asl, C. C. Cheung, Margaret Neuspiel, G.

MacLaurin, Andre Fortin, S. Park, Heidi M. McBride, and Ruth

S. Slack

From the Department of Cellular and Molecular Medicine, University

of Ottawa, Neurosciences Program, Ottawa Health Research Institute,

Ottawa, Ontario K1H 8M5, Canada and the University of Ottawa Heart

Institute, University of Ottawa, Ontario K1Y 4W7, Canada

Of the GTPases involved in the regulation of the fusion machinery,

mitofusin 2 (Mfn2) plays an important role in the nervous system as

point mutations of this isoform are associated with Charcot Marie

Tooth neuropathy. Here, we investigate whether Mfn2 plays a role in

the regulation of neuronal injury.

We first examine mitochondrial dynamics following different modes of

injury in cerebellar granule neurons. We demonstrate that neurons

exposed to DNA damage or oxidative stress exhibit extensive

mitochondrial fission, an early event preceding neuronal loss. The

extent of mitochondrial fragmentation and remodeling is variable and

depends on the mode and the severity of the death stimuli.

Interestingly, whereas mitofusin 2 loss of function significantly

induces cell death in the absence of any cell death stimuli,

expression of mitofusin 2 prevents cell death following DNA damage,

oxidative stress, and K+ deprivation induced apoptosis.

More importantly, whereas wild-type Mfn2 and the hydrolysis-

deficient mutant of Mfn2 (Mfn2RasG12V) function equally to promote

fusion and lengthening of mitochondria, the activated Mfn2RasG12V

mutant shows a significant increase in the protection of neurons

against cell death and release of proapoptotic factor cytochrome c.

These findings highlight a signaling role for Mfn2 in the regulation

of apoptosis that extends beyond its role in mitochondrial fusion.