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: 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

Cuproptosis-related gene signatures and immunological characterization in sepsis- associated acute lung injury

“…circ_UBE2D2 has been shown to target binding sites for multiple miRNAs associated with septic acute kidney injury, affecting disease progression 48 . ULK2 appears to have a tissue-speci c role in regulating autophagy and other cellular processes 49 . Recent studies have con rmed the co-expression of DLAT with immunostimulatory genes, as well as immune inhibitors, chemokines, and chemokine receptors 50 .…”

Myokine Musclin Is Critical for Exercise-Induced Cardiac Conditioning

“…Mitochondria respiratory function was assessed using an Oroboros Instruments Oxygraph 2K (Innsbruck, Austria) as described previously [ 102 ]. Cardiac fibers from a small piece of the endocardium (~15 mg) were dissected and separated into bundles in ice-cold BIOPS buffer (7.23 mM K2EGTA, 2.77 mM CaK2EGTA, 20 mM imidazole, Sigma-Aldrich, I2399), 0.5 mM DTT, 20 mM taurine, 5.7 mM ATP (Sigma-Aldrich, St. Louis, MI, USA, A7699), 14.3 mM phosphocreatine (Sigma-Aldrich, P7936), 6.56 mM MgCl 2 ·6H 2 O, and 50 mM MES hydrate, pH 7.1).…”

Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

“…More recently, the non-autophagic role of ULK1 may affect heart-related diseases, which enriches its broader role beyond autophagy in cellular signaling pathways. Recent studies have found that deletion of ULK1 in the adult heart accelerates the progression of cardiomyopathy and heart failure, interestingly not by affecting the ULK1-mediated autophagy pathway 274 . In addition, ROS can affect the progression of various cardiac diseases, including cardiac hypertrophy, myocardial contractility disorders, cardiac extracellular matrix remodeling, and arrhythmias.…”