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One of the hallmarks of doxorubicin-induced cytotoxicity is mitochondrial dysfunction. Despite intensive research over recent decades, there are no effective approaches for alleviating doxorubicin-induced cytotoxicity. Melatonin, a natural hormone that is primarily secreted by the pineal gland, is emerging as a promising adjuvant that protects against doxorubicin-induced cytotoxicity owing to its pharmaceutical effect of preserving mitochondrial integrity. However, the underlying mechanisms are far from completely understood. Here, we provide novel evidence that treatment of H9c2 cardiomyoblasts with doxorubicin strongly induced AMP-activated protein kinase \u03b12 (AMPK\u03b12), which translocated to mitochondria and interfered with their function and integrity, ultimately leading to cellular apoptosis. These phenomena were significantly blocked by melatonin treatment. The levels of AMPK\u03b12 in murine hearts were tightly associated with cardiotoxicity in the context of doxorubicin and melatonin treatment. Therefore, our study suggests that the maintenance of mitochondrial integrity is a key factor in reducing doxorubicin-induced cytotoxicity and indicates that AMPK\u03b12 may serve as a novel target in the design of cytoprotective combination therapies that include doxorubicin.<\/jats:p>","DOI":"10.1038\/s12276-020-00541-3","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T07:03:03Z","timestamp":1608274983000},"page":"2055-2068","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Melatonin prevents doxorubicin-induced cardiotoxicity through suppression of AMPK\u03b12-dependent mitochondrial damage"],"prefix":"10.1038","volume":"52","author":[{"given":"Goowon","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhyeok","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dang Hieu","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quynh Hoa","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonchae","family":"Choe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Insug","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Soo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2704-9547","authenticated-orcid":false,"given":"Joohun","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"541_CR1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1124\/pr.56.2.6","volume":"56","author":"G Minotti","year":"2004","unstructured":"Minotti, G., Menna, P., Salvatorelli, E., Cairo, G. & Gianni, L. 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