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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
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
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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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