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Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage

Myeloid cell leukemia-1 (Mcl-1) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that Mcl-1′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that Mcl-1 plays a regulato...

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Autores principales: Moyzis, Alexandra G., Lally, Navraj S., Liang, Wenjing, Najor, Rita H., Gustafsson, Åsa B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102819/
https://www.ncbi.nlm.nih.gov/pubmed/35563775
http://dx.doi.org/10.3390/cells11091469
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author Moyzis, Alexandra G.
Lally, Navraj S.
Liang, Wenjing
Najor, Rita H.
Gustafsson, Åsa B.
author_facet Moyzis, Alexandra G.
Lally, Navraj S.
Liang, Wenjing
Najor, Rita H.
Gustafsson, Åsa B.
author_sort Moyzis, Alexandra G.
collection PubMed
description Myeloid cell leukemia-1 (Mcl-1) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that Mcl-1′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that Mcl-1 plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether Mcl-1 regulates autophagy in the heart. We found that cardiac-specific overexpression of Mcl-1 had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, Mcl-1 did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of Mcl-1 increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via Mcl-1′s LC3-interacting regions and mutation of these sites significantly reduced Mcl-1-mediated mitochondrial clearance. We also found that Mcl-1 interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that Mcl-1 suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor.
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spelling pubmed-91028192022-05-14 Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage Moyzis, Alexandra G. Lally, Navraj S. Liang, Wenjing Najor, Rita H. Gustafsson, Åsa B. Cells Article Myeloid cell leukemia-1 (Mcl-1) is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that Mcl-1′s functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that Mcl-1 plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether Mcl-1 regulates autophagy in the heart. We found that cardiac-specific overexpression of Mcl-1 had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, Mcl-1 did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of Mcl-1 increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via Mcl-1′s LC3-interacting regions and mutation of these sites significantly reduced Mcl-1-mediated mitochondrial clearance. We also found that Mcl-1 interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that Mcl-1 suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor. MDPI 2022-04-27 /pmc/articles/PMC9102819/ /pubmed/35563775 http://dx.doi.org/10.3390/cells11091469 Text en © 2022 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
Moyzis, Alexandra G.
Lally, Navraj S.
Liang, Wenjing
Najor, Rita H.
Gustafsson, Åsa B.
Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
title Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
title_full Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
title_fullStr Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
title_full_unstemmed Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
title_short Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage
title_sort mcl-1 differentially regulates autophagy in response to changes in energy status and mitochondrial damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102819/
https://www.ncbi.nlm.nih.gov/pubmed/35563775
http://dx.doi.org/10.3390/cells11091469
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