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Protein degradation is principally controlled by the Ubiquitin-Proteasome System. Mule is an E3 ubiquitin ligase that regulates cellular growth, DNA repair and apoptosis to maintain normal tissue architecture. However, Mule\u2019s function in the heart has yet to be described. In a screen, we found reduced Mule expression in left ventricular samples from end-stage heart failure patients. Consequently, we generated conditional cardiac-specific Mule knockout (<jats:italic>Mule\u2009<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic>(<jats:italic>y<\/jats:italic>)<\/jats:sup><jats:italic>;mcm<\/jats:italic>) mice. Mule ablation in adult <jats:italic>Mule\u2009<\/jats:italic><jats:sup><jats:italic>fl<\/jats:italic>\/<jats:italic>fl<\/jats:italic>(<jats:italic>y<\/jats:italic>)<\/jats:sup><jats:italic>;mcm<\/jats:italic> mice prevented myocardial c-Myc polyubiquitination, leading to c-Myc accumulation and subsequent reduced expression of Pgc-1\u03b1, Pink1, and mitochondrial complex proteins. Furthermore, these mice developed spontaneous cardiac hypertrophy, left ventricular dysfunction, and early mortality. Co-deletion of Mule and c-Myc rescued this phenotype. Our data supports an indispensable role for Mule in cardiac homeostasis through the regulation of mitochondrial function via maintenance of Pgc-1\u03b1 and Pink1 expression and persistent negative regulation of c-Myc.<\/jats:p>","DOI":"10.1038\/srep41490","type":"journal-article","created":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T09:55:09Z","timestamp":1486029309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The E3 ligase Mule protects the heart against oxidative stress and mitochondrial dysfunction through Myc-dependent inactivation of Pgc-1\u03b1 and Pink1"],"prefix":"10.1038","volume":"7","author":[{"given":"Keith","family":"Dadson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Hauck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyue","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Grothe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak W.","family":"Mak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filio","family":"Billia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,2]]},"reference":[{"key":"BFsrep41490_CR1","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nrcardio.2016.25","volume":"13","author":"B Ziaeian","year":"2016","unstructured":"Ziaeian, B. & Fonarow, G. 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