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

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 inju...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-08, Vol.282 (33), p.23788-23798
Main Authors: Jahani-Asl, Arezu, Cheung, Eric C.C., Neuspiel, Margaret, MacLaurin, Jason G., Fortin, Andre, Park, David S., McBride, Heidi M., Slack, Ruth S.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cell Death
Cell Line
Cerebellum - cytology
Charcot-Marie-Tooth Disease - etiology
DNA Damage
GTP Phosphohydrolases
Humans
Membrane Fusion
Membrane Proteins - genetics
Membrane Proteins - physiology
Mice
Mitochondria - metabolism
Mitochondria - pathology
Mitochondria - ultrastructure
Mitochondrial Proteins - genetics
Mitochondrial Proteins - physiology
Neurons - cytology
Neurons - ultrastructure
Oxidative Stress
Transfection
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M703812200