Comprehensive ubiquitome analysis reveals persistent mitochondrial remodeling disruptions from doxorubicin-induced cardiotoxicity in aged CD-1 male mice
Year: 2025
Type: article
Abstract: 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 were sacrificed 2 months 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 γ coactivator 1 α, 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 months 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.
Source: Archives of Toxicology
Institutions: Universidade do Porto, LAQV Requimte, University of Aveiro, University of Trieste, Cooperativa de Ensino Superior Politécnico e Universitário, Unidade em Ciências Biomoleculares Aplicadas, Centro de Investigação em Actividade Física Saúde e Lazer, Unidade de Investigação em Toxicologia & Uma Só Saúde
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,690
Awards: Sem título, Unidade de Ciências Biomoleculares Aplicadas, Unidade de Ciências Biomoleculares Aplicadas, Inflammation and disruption of redox homeostasis (but not metabolism) significantly contribute to the cardiotoxic effects of mitoxantrone and doxorubicin: findings from in vitro and in vivo studies conducted on differently aged mice, Laboratório para a Investigação Integrativa e translacional em Saúde Populacional, Poisoning the heart with anticancer drugs: is metabolic bioactivation or aging promotion the link to the cardiotoxicity of anticancer drugs? New early putative biomarkers of cardiac damage for an earlier therapeutic approach, Centro de Investigação em Actividade Física, Saúde e Lazer, Can early biomarkers of aging predict the cardiotoxicity induced by doxorubicin and mitoxantrone? An Omics approach on early biomarkers of aging, Instituto para a Saúde e a Bioeconomia, Laboratório Associado para a Química Verde - Tecnologias e Processos Limpos
OpenAlex ID: W4408155745