Harris 2022 Autophagy
Harris MP, Zhang QJ, Cochran CT, Ponce J, Alexander S, Kronemberger A, Fuqua JD, Zhang Y, Fattal R, Harper T, Murry ML, Grueter CE, Abel ED, Lira VA (2022) Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function. https://doi.org/10.1080/15548627.2021.2022289 |
Β» Autophagy 18:2161-77. PMID: 35104184 Open Access
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 (2022) Autophagy
Abstract: 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. β’ Keywords: Age-related cardiomyopathy, MAP1LC3, NBR1, SQSTM1, Dilated cardiomyopathy, Heart failure, Mitochondria, Mitophagy β’ Bioblast editor: Plangger M β’ O2k-Network Lab: US IA Iowa City Abel ED
Labels: MiParea: Respiration, Genetic knockout;overexpression
Pathology: Cardiovascular, Myopathy
Organism: Mouse Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS
Pathway: F, N
HRR: Oxygraph-2k
2022-12