Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Warnsmann, Verena, Marschall, Lisa-Marie, Osiewacz, Heinz D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1783682685830430720
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
work_keys_str_mv AT warnsmannverena impairedf1foatpsynthasedimerizationleadstotheinductionofcyclophilindmediatedautophagydependentcelldeathandacceleratedaging
AT marschalllisamarie impairedf1foatpsynthasedimerizationleadstotheinductionofcyclophilindmediatedautophagydependentcelldeathandacceleratedaging
AT osiewaczheinzd impairedf1foatpsynthasedimerizationleadstotheinductionofcyclophilindmediatedautophagydependentcelldeathandacceleratedaging