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Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation
Mitochondria contain tens to thousands of copies of their own genome (mitochondrial DNA [mtDNA]), creating genetic redundancy capable of buffering mutations in mitochondrial genes essential for cellular function. However, the mechanisms regulating mtDNA copy number have been elusive. Here we found t...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940314/ https://www.ncbi.nlm.nih.gov/pubmed/29519802 http://dx.doi.org/10.1083/jcb.201801168 |
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author | Medeiros, Tânia Catarina Thomas, Ryan Lee Ghillebert, Ruben Graef, Martin |
author_facet | Medeiros, Tânia Catarina Thomas, Ryan Lee Ghillebert, Ruben Graef, Martin |
author_sort | Medeiros, Tânia Catarina |
collection | PubMed |
description | Mitochondria contain tens to thousands of copies of their own genome (mitochondrial DNA [mtDNA]), creating genetic redundancy capable of buffering mutations in mitochondrial genes essential for cellular function. However, the mechanisms regulating mtDNA copy number have been elusive. Here we found that DNA synthesis and degradation by mtDNA polymerase γ (POLG) dynamically controlled mtDNA copy number in starving yeast cells dependent on metabolic homeostasis provided by autophagy. Specifically, the continuous mtDNA synthesis by POLG in starving wild-type cells was inhibited by nucleotide insufficiency and elevated mitochondria-derived reactive oxygen species in the presence of autophagy dysfunction. Moreover, after prolonged starvation, 3′–5′ exonuclease–dependent mtDNA degradation by POLG adjusted the initially increasing mtDNA copy number in wild-type cells, but caused quantitative mtDNA instability and irreversible respiratory dysfunction in autophagy-deficient cells as a result of nucleotide limitations. In summary, our study reveals that mitochondria rely on the homeostatic functions of autophagy to balance synthetic and degradative modes of POLG, which control copy number dynamics and stability of the mitochondrial genome. |
format | Online Article Text |
id | pubmed-5940314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-59403142018-11-07 Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation Medeiros, Tânia Catarina Thomas, Ryan Lee Ghillebert, Ruben Graef, Martin J Cell Biol Research Articles Mitochondria contain tens to thousands of copies of their own genome (mitochondrial DNA [mtDNA]), creating genetic redundancy capable of buffering mutations in mitochondrial genes essential for cellular function. However, the mechanisms regulating mtDNA copy number have been elusive. Here we found that DNA synthesis and degradation by mtDNA polymerase γ (POLG) dynamically controlled mtDNA copy number in starving yeast cells dependent on metabolic homeostasis provided by autophagy. Specifically, the continuous mtDNA synthesis by POLG in starving wild-type cells was inhibited by nucleotide insufficiency and elevated mitochondria-derived reactive oxygen species in the presence of autophagy dysfunction. Moreover, after prolonged starvation, 3′–5′ exonuclease–dependent mtDNA degradation by POLG adjusted the initially increasing mtDNA copy number in wild-type cells, but caused quantitative mtDNA instability and irreversible respiratory dysfunction in autophagy-deficient cells as a result of nucleotide limitations. In summary, our study reveals that mitochondria rely on the homeostatic functions of autophagy to balance synthetic and degradative modes of POLG, which control copy number dynamics and stability of the mitochondrial genome. Rockefeller University Press 2018-05-07 /pmc/articles/PMC5940314/ /pubmed/29519802 http://dx.doi.org/10.1083/jcb.201801168 Text en © 2018 Medeiros et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Medeiros, Tânia Catarina Thomas, Ryan Lee Ghillebert, Ruben Graef, Martin Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation |
title | Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation |
title_full | Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation |
title_fullStr | Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation |
title_full_unstemmed | Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation |
title_short | Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation |
title_sort | autophagy balances mtdna synthesis and degradation by dna polymerase polg during starvation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940314/ https://www.ncbi.nlm.nih.gov/pubmed/29519802 http://dx.doi.org/10.1083/jcb.201801168 |
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