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Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria.


ABSTRACT: Proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 in mitochondria is emerging as a central regulatory hub that determines mitochondrial 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 Oma1 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.

SUBMITTER: Korwitz A 

PROVIDER: S-EPMC4738383 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria.

Korwitz Anne A   Merkwirth Carsten C   Richter-Dennerlein Ricarda R   Tröder Simon E SE   Sprenger Hans-Georg HG   Quirós Pedro M PM   López-Otín Carlos C   Rugarli Elena I EI   Langer Thomas T  

The Journal of cell biology 20160101 2


Proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 in mitochondria is emerging as a central regulatory hub that determines mitochondrial 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 neur  ...[more]

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2023-02-01 | GSE203234 | GEO