{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:01:04Z","timestamp":1785438064244,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL160969"],"award-info":[{"award-number":["R01HL160969"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R01HL160969"],"award-info":[{"award-number":["R01HL160969"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Doxorubicin (DOX) remains an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Mitochondrial dysfunction and metabolic remodeling are central features of DOX-induced cardiac injury. ATP synthase inhibitory factor-1 (IF1) is an endogenous inhibitor of the hydrolytic activity of mitochondrial ATP synthase and has emerged as an important regulator of cellular bioenergetics. Cardiac IF1 expression is increased in multiple pathological conditions; however, its role in chemotherapy-induced cardiotoxicity remains unclear. Here, we investigated the contribution of IF1 to DOX-induced cardiotoxicity using male C57BL\/6J wild-type (WT) and IF1 knockout (IF1KO) mice, isolated cardiac mitochondria, cultured neonatal cardiomyocytes, and AC16 human cardiomyocytes. Cardiac function was assessed by echocardiography, mitochondrial function by high-resolution respirometry and Seahorse metabolic flux analysis, and myocardial injury by histological and ultrastructural analyses. DOX treatment markedly increased cardiac IF1 protein levels despite reduced IF1 mRNA expression. IF1 deficiency enhanced mitochondrial respiration in isolated cardiac mitochondria and cultured cardiomyocytes under both basal and DOX-stressed conditions. IF1KO mice exhibited attenuated cardiac dysfunction and improved myocardial ultrastructure following DOX treatment compared with WT mice. In AC16 cardiomyocytes exposed to DOX, overexpression of WT IF1 improved cellular metabolic activity but provided only limited preservation of mitochondrial respiratory capacity. In contrast, overexpression of the dominant-negative IF1 mutant (IF1E30A) not only improved metabolic activity but also preserved mitochondrial respiration. These findings identify IF1 as a key regulator of metabolic adaptation during DOX stress. Upregulation of functional IF1 may represent an adaptive response that promotes glycolytic ATP production during mitochondrial stress, whereas inhibition of IF1 activity preserves metabolic activity primarily through maintenance of mitochondrial function. Collectively, these findings provide new insights into the role of IF1 in DOX-induced cardiomyopathy and highlight IF1 as a potential therapeutic target in cardio-oncology.<\/jats:p>","DOI":"10.3390\/ijms27146360","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:54:13Z","timestamp":1784534053000},"page":"6360","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ATP Synthase Inhibitory Factor-1 Deficiency Attenuates Doxorubicin Cardiotoxicity by Preserving Mitochondrial Structure and Function"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3582-1669","authenticated-orcid":false,"given":"Parnia","family":"Mobasheran","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, School of Graduate Studies, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1691-5112","authenticated-orcid":false,"given":"Ankit","family":"Aryal","sequence":"additional","affiliation":[{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmine","family":"Aguilar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, School of Graduate Studies, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0018-6909","authenticated-orcid":false,"given":"Scott","family":"Jennings","sequence":"additional","affiliation":[{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar","family":"Lauterboeck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, School of Graduate Studies, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kati","family":"Young","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6024-2517","authenticated-orcid":false,"given":"Qinglin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, School of Graduate Studies, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"},{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1136\/heartjnl-2017-312103","article-title":"Anthracycline cardiotoxicity: An update on mechanisms, monitoring and prevention","volume":"104","author":"Henriksen","year":"2018","journal-title":"Heart"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1093\/jpp\/rgac063","article-title":"Doxorubicin-induced cardiotoxicity: Causative factors and possible interventions","volume":"74","author":"Jones","year":"2022","journal-title":"J. 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