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The objective of this study was to assess the enduring cardiac molecular impacts of DOX in old CD-1 male mice, focusing on ubiquitinated proteins. At 19\u00a0months of age, DOX group received a cumulative dose of 9.0\u00a0mg\/kg of DOX, while control animals got saline solution. Animals were sacrificed 2\u00a0months after the administration. DOX induced heart structural changes and increased proteolytic activity. Additionally, increased protein ubiquitination was observed in DOX group, despite the decreased content of the E3 ubiquitin-protein ligase Atrogin-1. A search of poly-ubiquitinated proteins, enriched by tandem ubiquitin-binding entities (TUBEs), showed increased poly-ubiquitination of proteins associated with sarcomere organization and mitochondrial metabolism processes by DOX. Increased mitochondrial density inferred by higher citrate synthase activity was found in DOX group. Moreover, decreased biogenesis and auto(mito)phagy occurred in DOX animals, proven by decreased peroxisome proliferator-activated receptor \u03b3 coactivator 1 \u03b1, Beclin1 and microtubule-associated protein light chain 3 content. These findings indicate a reduction in mitochondrial biogenesis and accumulation of dysfunctional mitochondria in the aged heart, along with elevated levels of poly-ubiquitinated proteins after DOX treatment. Thus, the disruption of mitochondrial remodeling and impaired protein ubiquitination emerge as enduring consequences of DOX-induced cardiotoxicity, persisting for even 2\u00a0months after DOX exposure. This underscores the long-lasting impact of DOX, with significant effects continuing beyond the period of administration, which advocates for longer clinical surveillance.<\/jats:p>","DOI":"10.1007\/s00204-025-04006-2","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T05:48:16Z","timestamp":1741067296000},"page":"2447-2462","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comprehensive ubiquitome analysis reveals persistent mitochondrial remodeling disruptions from doxorubicin-induced cardiotoxicity in aged CD-1 male mice"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9964-8947","authenticated-orcid":false,"given":"Sofia Reis","family":"Brand\u00e3o","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-7525","authenticated-orcid":false,"given":"Elisa","family":"Lazzari","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-5805","authenticated-orcid":false,"given":"Rui","family":"Vitorino","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2531-114X","authenticated-orcid":false,"given":"Germana","family":"Meroni","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-3147","authenticated-orcid":false,"given":"Ana","family":"Reis-Mendes","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1464-8700","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Neuparth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-1749","authenticated-orcid":false,"given":"Francisco","family":"Amado","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3494","authenticated-orcid":false,"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-4051","authenticated-orcid":false,"given":"Rita","family":"Ferreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-2756","authenticated-orcid":false,"given":"Vera Marisa","family":"Costa","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"4006_CR1","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.yjmcc.2022.08.136","volume":"173","author":"C Abrahams","year":"2022","unstructured":"Abrahams C, Woudberg NJ, Kodogo V et al (2022) Doxorubicin-induced cardiotoxicity is associated with a change in high density lipoprotein subclasses in a mouse breast cancer model. 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