{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:33:01Z","timestamp":1787027581163,"version":"build-2736575974"},"reference-count":27,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270296"],"award-info":[{"award-number":["82270296"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81470510"],"award-info":[{"award-number":["81470510"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2020JM-029"],"award-info":[{"award-number":["2020JM-029"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["82270296"],"award-info":[{"award-number":["82270296"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["81470510"],"award-info":[{"award-number":["81470510"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["2020JM-029"],"award-info":[{"award-number":["2020JM-029"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Recent studies have shown that FMS-like receptor tyrosine kinase 3 (Flt3) has a beneficial effect on cardiac maladaptive remodeling. However, the role and mechanism of Flt3 in mitochondrial dynamic imbalance under cardiac stress remains poorly understood. This study aims to investigate how Flt3 regulates p53-mediated optic atrophy 1 (OPA1) processing and mitochondrial fragmentation to improve cardiac remodeling. Mitochondrial fragmentation in cardiomyocytes was induced by isoprenaline (ISO) and H2O2 challenge, respectively, in vitro. Cardiac remodeling in mice was established by ligating the left anterior descending coronary artery or by chronic ISO challenge, respectively, in vivo. Our results demonstrated that the protein expression of acetylated-p53 (ac-p53) in mitochondria was significantly increased under cell stress conditions, facilitating the dissociation of PHB2-OPA1 complex by binding to prohibitin 2 (PHB2), a molecular chaperone that stabilizes OPA1 in mitochondria. This led to the degradation of the long isoform of OPA1 (L-OPA1) that facilitates mitochondrial fusion and resultant mitochondrial network fragmentation. This effect was abolished by a p53 K371R mutant that failed to bind to PHB2 and impeded the formation of the ac-p53-PHB2 complex. The activation of Flt3 significantly reduced ac-p53 expression in mitochondria via SIRT1, thereby hindering the formation of the ac-p53-PHB2 complex and potentiating the stability of the PHB2-OPA1 complex. This ultimately inhibits L-OPA1 processing and leads to the balancing of mitochondrial dynamics. These findings highlight a novel mechanism by which Flt3 activation mitigates mitochondrial fragmentation and dysfunction through the reduction of L-OPA1 processing by dampening the interaction between ac-p53 and PHB2 in cardiac maladaptive remodeling.<\/jats:p>","DOI":"10.3390\/antiox12091657","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T08:58:54Z","timestamp":1692694734000},"page":"1657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Flt3 Activation Mitigates Mitochondrial Fragmentation and Heart Dysfunction through Rebalanced L-OPA1 Processing by Hindering the Interaction between Acetylated p53 and PHB2 in Cardiac Remodeling"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5643-2333","authenticated-orcid":false,"given":"Kaina","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2814-0881","authenticated-orcid":false,"given":"Yeqing","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5424-3339","authenticated-orcid":false,"given":"Gaowa","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8670-0662","authenticated-orcid":false,"given":"Wenzhuo","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5494-6321","authenticated-orcid":false,"given":"Bing","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwen","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0421-2046","authenticated-orcid":false,"given":"Zhenghang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/978-3-319-55330-6_15","article-title":"Mitochondria in Structural and Functional Cardiac Remodeling","volume":"982","author":"Torrealba","year":"2017","journal-title":"Adv. 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