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

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Mitofusin 2 Protects Cerebellar Granule Neurons against Injury-induced Cell Death^*

Arezu Jahani-Asl, Eric C. C. Cheung, Margaret Neuspiel, Jason G. MacLaurin, Andre Fortin, David S. Park, Heidi M. McBride¹, and Ruth S. Slack²

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 (Mfn2_RasG12V) function equally to promote fusion and lengthening of mitochondria, the activated Mfn2_RasG12V 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.

Received for publication, May 9, 2007

^* This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and Heart and Stroke Foundation of Canada (HSFC) (to R. S. S.). A. J.-A., E. C. C. C., and A. F. are supported by CIHR studentships. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Movies 1–5.

¹ To whom correspondence may be addressed: University of Ottawa Heart Inst., University of Ottawa, 40 Ruskin St., Rm. H445A, Ontario K1Y 4W7, Canada. E-mail: hmcbride{at}ottawaheart.ca. ² To whom correspondence may be addressed: Ottawa Health Research Inst., University of Ottawa, 451 Smyth Rd., Rm. 2452, Ottawa, Ontario K1H 8M5, Canada. E-mail: rslack{at}uottawa.ca.

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