title: 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.
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Korwitz
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Merkwirth
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Richter-Dennerlein
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Tröder
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sprenger
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Quirós
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33006, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
authors.affiliation: Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany Max Planck Institute for Biology of Aging, 50931 Cologne, Germany thomas.langer@uni-koeln.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D017353:Gene Deletion; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000091402:Prohibitins; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000091402:Prohibitins; D012097:Repressor Proteins; D045726:Metalloproteases; C572960:OMA1 protein, mouse; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse