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 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.
Jahani-Asl
Arezu
A
Department of Cellular and Molecular Medicine, University of Ottawa, Neurosciences Program, Ottawa Health Research Institute, Ottawa, Ontario K1H 8M5, Canada.
Cheung
Eric C C
EC
Neuspiel
Margaret
M
MacLaurin
Jason G
JG
Fortin
Andre
A
Park
David S
DS
McBride
Heidi M
HM
Slack
Ruth S
RS
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D002531:Cerebellum / Q000166:cytology*; D002607:Charcot-Marie-Tooth Disease / Q000209:etiology; D004249:DNA Damage; D020558:GTP Phosphohydrolases; D006801:Humans; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000648:ultrastructure*; D018384:Oxidative Stress; D014162:Transfection
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human