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The molecular mechanism mediating mitophagy during pressure overload (PO) is poorly understood. We have shown previously that mitophagy in the heart is mediated primarily by Atg5\/Atg7-independent mechanisms, including Unc-51-like kinase 1 (Ulk1)-dependent alternative mitophagy, during myocardial ischaemia. Here, we investigated the role of alternative mitophagy in the heart during PO-induced hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Mitophagy was observed in the heart in response to transverse aortic constriction (TAC), peaking at 3\u20135 days. Whereas mitophagy is transiently up-regulated by TAC through an Atg7-dependent mechanism in the heart, peaking at 1 day, it is also activated more strongly and with a delayed time course through an Ulk1-dependent mechanism. TAC induced more severe cardiac dysfunction, hypertrophy, and fibrosis in ulk1 cardiac-specific knock-out (cKO) mice than in wild-type mice. Delayed activation of mitophagy was characterized by the co-localization of Rab9 dots and mitochondria and phosphorylation of Rab9 at Ser179, major features of alternative mitophagy. Furthermore, TAC-induced decreases in the mitochondrial aspect ratio were abolished and the irregularity of mitochondrial cristae was exacerbated, suggesting that mitochondrial quality control mechanisms are impaired in ulk1 cKO mice in response to TAC. TAT-Beclin 1 activates mitophagy even in Ulk1-deficient conditions. TAT-Beclin 1 treatment rescued mitochondrial dysfunction and cardiac dysfunction in ulk1 cKO mice during PO.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Ulk1-mediated alternative mitophagy is a major mechanism mediating mitophagy in response to PO and plays an important role in mediating mitochondrial quality control mechanisms and protecting the heart against cardiac dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvac003","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T23:18:33Z","timestamp":1641511113000},"page":"2638-2651","source":"Crossref","is-referenced-by-count":66,"title":["Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2254-2233","authenticated-orcid":false,"given":"Jihoon","family":"Nah","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ ,","place":["USA"]},{"name":"School of Biological Sciences, Seoul National University , Seoul ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Shirakabe","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ ,","place":["USA"]},{"name":"Nippon Medical School, Chiba Hokusoh Hospital , Chiba ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4669-4100","authenticated-orcid":false,"given":"Risa","family":"Mukai","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6482-2033","authenticated-orcid":false,"given":"Peiyong","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1843-0338","authenticated-orcid":false,"given":"Eun Ah","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7578-1337","authenticated-orcid":false,"given":"Andreas","family":"Ivessa","sequence":"additional","affiliation":[{"name":"Department of Cell 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Newark, NJ ,","place":["USA"]},{"name":"Department of Surgery and Clinical Science, Graduate School of Medicine, Yamaguchi University , Ube, Yamaguchi ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9957-9256","authenticated-orcid":false,"given":"Chengchen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School , Newark, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Keun","family":"Jung","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Seoul National University , Seoul ,","place":["Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-4132","authenticated-orcid":false,"given":"Junichi","family":"Sadoshima","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular 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