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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 mi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738383/ https://www.ncbi.nlm.nih.gov/pubmed/26783299 http://dx.doi.org/10.1083/jcb.201507022 |
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author | Korwitz, Anne Merkwirth, Carsten Richter-Dennerlein, Ricarda Tröder, Simon E. Sprenger, Hans-Georg Quirós, Pedro M. López-Otín, Carlos Rugarli, Elena I. Langer, Thomas |
author_facet | Korwitz, Anne Merkwirth, Carsten Richter-Dennerlein, Ricarda Tröder, Simon E. Sprenger, Hans-Georg Quirós, Pedro M. López-Otín, Carlos Rugarli, Elena I. Langer, Thomas |
author_sort | Korwitz, Anne |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4738383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-47383832016-07-18 Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria Korwitz, Anne Merkwirth, Carsten Richter-Dennerlein, Ricarda Tröder, Simon E. Sprenger, Hans-Georg Quirós, Pedro M. López-Otín, Carlos Rugarli, Elena I. Langer, Thomas J Cell Biol Research Articles 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. The Rockefeller University Press 2016-01-18 /pmc/articles/PMC4738383/ /pubmed/26783299 http://dx.doi.org/10.1083/jcb.201507022 Text en © 2016 Korwitz et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Korwitz, Anne Merkwirth, Carsten Richter-Dennerlein, Ricarda Tröder, Simon E. Sprenger, Hans-Georg Quirós, Pedro M. López-Otín, Carlos Rugarli, Elena I. Langer, Thomas Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria |
title | Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria |
title_full | Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria |
title_fullStr | Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria |
title_full_unstemmed | Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria |
title_short | Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria |
title_sort | loss of oma1 delays neurodegeneration by preventing stress-induced opa1 processing in mitochondria |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738383/ https://www.ncbi.nlm.nih.gov/pubmed/26783299 http://dx.doi.org/10.1083/jcb.201507022 |
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