ausblenden:
Schlagwörter:
Animals
Apoptosis
Brain/metabolism/pathology
Cell Respiration
Cell Survival/genetics
Cells, Cultured
DNA, Mitochondrial/metabolism
GTP Phosphohydrolases/*metabolism
Gene Deletion
Metalloproteases/*genetics/metabolism
Mice
Mice, Inbred C57BL
Mitochondria/*metabolism
Mitochondrial Proteins/*genetics/metabolism
*Nerve Degeneration/genetics
Neurons/metabolism/pathology
Repressor Proteins/metabolism
Zusammenfassung:
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.
