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Ubiquitome profiling uncovers disturbed mitochondrial remodeling as an outcome of doxorubicin-induced cardiotoxicity in old mice

ABSTRACT: The urgent need to understand the molecular modulation associated with chronic cardiotoxicity of doxorubicin (DOX) has prompted us to investigate the ubiquitome profile of aged cardiac muscle. Using old CD-1 male mice administered with a DOX dosage established to induce cardiotoxicity, we performed a comprehensive analysis of the proteomic profile of the enriched pool of poly-ubiquitinated proteins obtained from cardiac muscle using tandem ubiquitin-binding entities (TUBEs). GeLC-MS/MS and subsequent bioinformatic analysis revealed several proteins with the poly-ubiquitination modification involved in DOX-induced cardiotoxicity. Increased poly-ubiquitination levels were found for sarcomeric proteins including alpha-actinin-2 and desmin as well as mitochondrial proteins such as ATP synthase subunit beta and cytochrome b-c1 complex subunit 1. Thus, impaired protein ubiquitination emerges as an enduring consequence of DOX-induced cardiotoxicity. The present exploratory analysis could be considered an important starting point for further studies targeting molecular pathways under the side effects of the widely used anticancer drug DOX.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Rui Vitorino

LAB HEAD: Rui Vitorino

PROVIDER: PXD048078 | Pride | 2025-06-30

REPOSITORIES: Pride

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Comprehensive ubiquitome analysis reveals persistent mitochondrial remodeling disruptions from doxorubicin-induced cardiotoxicity in aged CD-1 male mice.

Brandão Sofia Reis SR Lazzari Elisa E Vitorino Rui R Meroni Germana G Reis-Mendes Ana A Neuparth Maria João MJ Amado Francisco F Carvalho Félix F Ferreira Rita R Costa Vera Marisa VM

Archives of toxicology 20250304 6

Doxorubicin (DOX)-associated cardiotoxicity is characterized by long-term manifestations, whose mechanisms remain incompletely understood, and is exacerbated by various risk factors, with age being a prominent contributor. 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 months of age, DOX group received a cumulative dose of 9.0 mg/kg of DOX, while control animals got saline solution. Animals ...[more]

PMID: 40035845

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