{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:18:28Z","timestamp":1790565508441,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,9,22]],"date-time":"2024-09-22T00:00:00Z","timestamp":1726963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>N6\u2010methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis\u2010induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)\u2010induced myocardial injury. This study aimed to investigate the impact of LPS\u2010induced endotoxemia on m6A\u2010RNA methylation and its role in regulating mitophagy in sepsis\u2010induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity\u2010associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno\u2010associated virus serotype 9 (AAV9)\u2010mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV\u2010FTO were significantly compromised by mdivi\u20101, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A\u2010dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521\u2010B homology m6A RNA\u2010binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO\u2010dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.<\/jats:p>","DOI":"10.1002\/jcp.31448","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T06:04:56Z","timestamp":1727071496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["N6\u2010methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy"],"prefix":"10.1002","volume":"239","author":[{"given":"Pingping","family":"Qi","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital of Guangxi Medical University Blood Transfusion Department Nanning 533000 Guangxi People's Repulic of 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