Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac
autophagy and function.
Authors 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
Submitted By Submitted Externally on 10/5/2022
Status Published
Journal Autophagy
Year 2022
Date Published 9/1/2022
Volume : Pages 18 : 2161 - 2177
PubMed Reference 35104184
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: 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.