Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function.

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.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 NADHubiquinone 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.