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Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function
Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to pl...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Taylor & Francis
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9466614/ https://www.ncbi.nlm.nih.gov/pubmed/35104184 http://dx.doi.org/10.1080/15548627.2021.2022289 |
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author | Harris, Matthew P. Zhang, Quan J. Cochran, Cole T. Ponce, Jessica Alexander, Sean Kronemberger, Ana Fuqua, Jordan D. Zhang, Yuan Fattal, Ranan Harper, Tyler Murry, Matthew L. Grueter, Chad E. Abel, E. Dale Lira, Vitor A. |
author_facet | Harris, Matthew P. Zhang, Quan J. Cochran, Cole T. Ponce, Jessica Alexander, Sean Kronemberger, Ana Fuqua, Jordan D. Zhang, Yuan Fattal, Ranan Harper, Tyler Murry, Matthew L. Grueter, Chad E. Abel, E. Dale Lira, Vitor A. |
author_sort | Harris, Matthew P. |
collection | PubMed |
description | Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to play primarily redundant roles in autophagy initiation, but whether their function is developmentally determined, potentially having an impact on cardiac integrity and function remains unknown. Here, we demonstrate that perinatal loss of ULK1 or ULK2 in cardiomyocytes (cU1-KO and cU2-KO mice, respectively) enhances basal autophagy without altering autophagy machinery content while preserving cardiac function. This increased basal autophagy is dependent on the remaining ULK protein given that perinatal loss of both ULK1 and ULK2 in cU1/2-DKO mice impaired autophagy causing age-related cardiomyopathy and reduced survival. Conversely, adult loss of cardiac ULK1, but not of ULK2 (i.e., icU1-KO and icU2-KO mice, respectively), led to a rapidly developing cardiomyopathy, heart failure and early death. icU1-KO mice had impaired autophagy with robust deficits in mitochondrial respiration and ATP synthesis. Trehalose ameliorated autophagy impairments in icU1-KO hearts but did not delay cardiac dysfunction suggesting that ULK1 plays other critical, autophagy-independent, functions in the adult heart. Collectively, these results indicate that cardiac ULK1 and ULK2 are functionally redundant in the developing heart, while ULK1 assumes a more unique, prominent role in the adult heart. Abbreviations: ATG4: autophagy related 4, cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; ATG13: autophagy related 13; CYCS: Cytochrome C; DNM1L, dynamin 1-like; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MFN2: mitofusin 2; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MYH: myosin, heavy polypeptide; NBR1: NBR1 autophagy cargo receptor; NDUFA9: NADH:ubiquinone oxidoreductase subunit A9; OPA1: OPA1, mitochondrial dynamin like GTPase; PPARGC1A, peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; SDHA: succinate dehydrogenase complex, subunit A, flavoprotein (Fp); SQSTM1: sequestosome 1; ULK1: unc-51 like kinase 1; ULK2: unc-51 like kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1 |
format | Online Article Text |
id | pubmed-9466614 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-94666142022-09-13 Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function Harris, Matthew P. Zhang, Quan J. Cochran, Cole T. Ponce, Jessica Alexander, Sean Kronemberger, Ana Fuqua, Jordan D. Zhang, Yuan Fattal, Ranan Harper, Tyler Murry, Matthew L. Grueter, Chad E. Abel, E. Dale Lira, Vitor A. Autophagy Research Paper Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to play primarily redundant roles in autophagy initiation, but whether their function is developmentally determined, potentially having an impact on cardiac integrity and function remains unknown. Here, we demonstrate that perinatal loss of ULK1 or ULK2 in cardiomyocytes (cU1-KO and cU2-KO mice, respectively) enhances basal autophagy without altering autophagy machinery content while preserving cardiac function. This increased basal autophagy is dependent on the remaining ULK protein given that perinatal loss of both ULK1 and ULK2 in cU1/2-DKO mice impaired autophagy causing age-related cardiomyopathy and reduced survival. Conversely, adult loss of cardiac ULK1, but not of ULK2 (i.e., icU1-KO and icU2-KO mice, respectively), led to a rapidly developing cardiomyopathy, heart failure and early death. icU1-KO mice had impaired autophagy with robust deficits in mitochondrial respiration and ATP synthesis. Trehalose ameliorated autophagy impairments in icU1-KO hearts but did not delay cardiac dysfunction suggesting that ULK1 plays other critical, autophagy-independent, functions in the adult heart. Collectively, these results indicate that cardiac ULK1 and ULK2 are functionally redundant in the developing heart, while ULK1 assumes a more unique, prominent role in the adult heart. Abbreviations: ATG4: autophagy related 4, cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; ATG13: autophagy related 13; CYCS: Cytochrome C; DNM1L, dynamin 1-like; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MFN2: mitofusin 2; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MYH: myosin, heavy polypeptide; NBR1: NBR1 autophagy cargo receptor; NDUFA9: NADH:ubiquinone oxidoreductase subunit A9; OPA1: OPA1, mitochondrial dynamin like GTPase; PPARGC1A, peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; SDHA: succinate dehydrogenase complex, subunit A, flavoprotein (Fp); SQSTM1: sequestosome 1; ULK1: unc-51 like kinase 1; ULK2: unc-51 like kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1 Taylor & Francis 2022-02-01 /pmc/articles/PMC9466614/ /pubmed/35104184 http://dx.doi.org/10.1080/15548627.2021.2022289 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Research Paper Harris, Matthew P. Zhang, Quan J. Cochran, Cole T. Ponce, Jessica Alexander, Sean Kronemberger, Ana Fuqua, Jordan D. Zhang, Yuan Fattal, Ranan Harper, Tyler Murry, Matthew L. Grueter, Chad E. Abel, E. Dale Lira, Vitor A. Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function |
title | Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function |
title_full | Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function |
title_fullStr | Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function |
title_full_unstemmed | Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function |
title_short | Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function |
title_sort | perinatal versus adult loss of ulk1 and ulk2 distinctly influences cardiac autophagy and function |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9466614/ https://www.ncbi.nlm.nih.gov/pubmed/35104184 http://dx.doi.org/10.1080/15548627.2021.2022289 |
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