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Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging
Mitochondrial F(1)F(o)-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F(1)F(o)-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increa...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066942/ https://www.ncbi.nlm.nih.gov/pubmed/33808173 http://dx.doi.org/10.3390/cells10040757 |
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author | Warnsmann, Verena Marschall, Lisa-Marie Osiewacz, Heinz D. |
author_facet | Warnsmann, Verena Marschall, Lisa-Marie Osiewacz, Heinz D. |
author_sort | Warnsmann, Verena |
collection | PubMed |
description | Mitochondrial F(1)F(o)-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F(1)F(o)-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F(1)F(o)-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging. |
format | Online Article Text |
id | pubmed-8066942 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80669422021-04-25 Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging Warnsmann, Verena Marschall, Lisa-Marie Osiewacz, Heinz D. Cells Article Mitochondrial F(1)F(o)-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F(1)F(o)-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F(1)F(o)-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging. MDPI 2021-03-30 /pmc/articles/PMC8066942/ /pubmed/33808173 http://dx.doi.org/10.3390/cells10040757 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Warnsmann, Verena Marschall, Lisa-Marie Osiewacz, Heinz D. Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging |
title | Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging |
title_full | Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging |
title_fullStr | Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging |
title_full_unstemmed | Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging |
title_short | Impaired F(1)F(o)-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging |
title_sort | impaired f(1)f(o)-atp-synthase dimerization leads to the induction of cyclophilin d-mediated autophagy-dependent cell death and accelerated aging |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066942/ https://www.ncbi.nlm.nih.gov/pubmed/33808173 http://dx.doi.org/10.3390/cells10040757 |
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