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

2016 | journal article

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​Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria​
Korwitz, A.; Merkwirth, C.; Richter-Dennerlein, R. ; Tröder, S. E.; Sprenger, H.-G.; Quirós, P. M. & López-Otín, C. et al.​ (2016) 
Journal of Cell Biology212(2) pp. 157​-166​.​ DOI: https://doi.org/10.1083/jcb.201507022 

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Authors
Korwitz, Anne; Merkwirth, Carsten; Richter-Dennerlein, Ricarda ; Tröder, Simon E.; Sprenger, Hans-Georg; Quirós, Pedro M.; López-Otín, Carlos; Rugarli, Elena I.; Langer, Thomas
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.
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.
Issue Date
2016
Journal
Journal of Cell Biology 
ISSN
0021-9525
eISSN
1540-8140
Language
English

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