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

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.

Korwitz A ，Merkwirth C ，Richter-Dennerlein R ，Tröder SE ，Sprenger HG ，Quirós PM ，López-Otín C ，Rugarli EI ，Langer T ... -  《-》

Prohibitin levels regulate OMA1 activity and turnover in neurons.

Anderson CJ ，Kahl A ，Fruitman H ，Qian L ，Zhou P ，Manfredi G ，Iadecola C ... -  《-》

The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission.

Anand R ，Wai T ，Baker MJ ，Kladt N ，Schauss AC ，Rugarli E ，Langer T ... -  《-》

Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1.

Ehses S ，Raschke I ，Mancuso G ，Bernacchia A ，Geimer S ，Tondera D ，Martinou JC ，Westermann B ，Rugarli EI ，Langer T ... -  《-》

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Fogo GM ，Raghunayakula S ，Emaus KJ ，Torres Torres FJ ，Wider JM ，Sanderson TH ... -  《-》