Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function.
Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function.
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DOI：
10.1080/15548627.2021.2022289
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发表时间：
2022-09
期刊：
影响因子：
13.3
通讯作者：
Lira, Vitor A.
中科院分区：
文献类型：
--
作者：
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.
关键词：
巨噬/自噬损伤会降解功能失调的细胞器以及长寿命和聚集蛋白，这与几种心肌病有关；然而，对心脏自噬的调控仍知之甚少。在这方面，ULK1和ULK2被认为在自噬起始中起着主要的冗余作用，但它们的功能是否由发育决定，是否对心脏完整性和功能有潜在的影响尚不清楚。在这里，我们证明围产期心肌细胞（分别为cU1-KO和cU2-KO小鼠）中ULK1或ULK2的缺失增强了基础自噬，而不改变自噬机制的内容，同时保持了心功能。鉴于cU1/2-DKO小鼠围产期ULK1和ULK2的缺失会损害自噬，导致年龄相关性心肌病和生存率降低，这种增加的基础自噬依赖于剩余的ULK蛋白。相反，成人心脏ULK1缺失而ULK2缺失（分别为icU1-KO和icU2-KO小鼠）会导致心肌病、心力衰竭和早期死亡的快速发展。icU1-KO小鼠自噬受损，线粒体呼吸和ATP合成严重缺陷。海藻糖改善了icU1-KO心脏的自噬损伤，但没有延缓心功能障碍，这表明ULK1在成人心脏中起着其他关键的、不依赖于自噬的功能。总的来说，这些结果表明，心脏ULK1和ULK2在发育中的心脏中功能冗余，而ULK1在成人心脏中扮演着更独特、更突出的角色。缩写：ATG4：自噬相关4，半胱氨酸肽酶；ATG5：自噬相关5；ATG7：自噬相关7；ATG9：自噬相关9；ATG13：自噬相关13；CYCS：细胞色素C；DNM1L, dynamin 1-like；MAP1LC3A：微管相关蛋白1轻链3 α；MAP1LC3B：微管相关蛋白1轻链3 β；MFN1: mitofusin 1；MFN2：有丝分裂蛋白2；MT-CO1：线粒体编码细胞色素c氧化酶I；MYH：肌球蛋白，重多肽；NBR1: NBR1自噬货物受体；NADH：泛醌氧化还原酶亚基A9；OPA1：线粒体动力蛋白样GTPase；PPARGC1A，过氧化物酶体增殖物激活受体，γ，辅激活因子1 α；SDHA：琥珀酸脱氢酶复合物，亚基A，黄蛋白（Fp）；SQSTM1: sequestosome 1；ULK1: unc-51样激酶1；ULK2: unc-51样激酶2；UQCRC1：泛醇-细胞色素c还原酶核心蛋白
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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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1083/jcb.111.6.2427
发表时间：
1990-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lyons GE;Schiaffino S;Sassoon D;Barton P;Buckingham M
通讯作者：
Buckingham M
影响因子：
13.3
作者：
Lee, Eunmyong;Koo, Yeon;Amatruda, James F.
通讯作者：
Amatruda, James F.
影响因子：
16.6
作者：
Laker RC;Drake JC;Wilson RJ;Lira VA;Lewellen BM;Ryall KA;Fisher CC;Zhang M;Saucerman JJ;Goodyear LJ;Kundu M;Yan Z
通讯作者：
Yan Z