期刊
JOURNAL OF CELL BIOLOGY
卷 212, 期 2, 页码 157-166出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201507022
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资金
- European Molecular Biology Organization long-term fellowship
- Deutsche Forschungsgemeinschaft
- European Research Council
- Ministerio de Economia y Competitividad (Spain)
- Fundacion Bancaria Caja de Ahorros de Asturias
- Banco Santander through its Santander Universities Global Division
Proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 in mitochondria is emerging as a central regulatory hub that determines mitochondria! morphology under stress and in disease. Stress-induced OPA1 processing by OMA1 triggersmitochondrial fragmentation, which is associated with mitophagy and apoptosis in vitro. Here, we identify OMA1 as a critical regulator of neuronal survival in vivo and demonstrate that stress-induced OPA1 processing by OMA1 promotes neuronal death and neuroinflammatory responses. Using mice lacking prohibitin membrane scaffolds as a model of neurodegeneration, we demonstrate that additional ablation of Oma 1 delays neuronal loss and prolongs lifespan. This is accompanied by the accumulation of fusion-active, long OPA1 forms, which stabilize the mitochondrial genome but do not preserve mitochondrial cristae or respiratory chain supercomplex assembly in prohibitin-depleted neurons. Thus, long OPA1 forms can promote neuronal survival independently of cristae shape, whereas stress-induced OMA1 activation and OPA1 cleavage limit mitochondrial fusion and promote neuronal death.
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