MitoQ reduces senescence burden in Doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage

Cardiovascular toxicity is one of the adverse consequences of chemotherapy, limiting its therapeutic application. Chemotherapeutics, such as doxorubicin (DOXO), induce endothelial dysfunction via genotoxic effects, and reactive oxygen species (ROS) and mitochondrial ROS (mtROS) generation. These mechanisms increase DNA damage and cellular senescence, a persistent cell cycle arrest promoting inflammation, which elevates future cardiovascular disease risk. The adverse impact of DOXO on endothelial function can be mitigated by the mitochondria-targeted antioxidant, MitoQ; however, its precise protective mechanism in endothelial cells (ECs) remains unclear. The present study hypothesizes that co-treating ECs with MitoQ and DOXO attenuates DOXO-induced mtROS, thereby reducing DNA damage, senescence, and inflammation. Mitochondrial superoxide levels, mitochondrial mass, DNA damage, and cellular senescence were assessed in human umbilical vein ECs (HUVECs) 48 hours after DOXO and/or MitoQ treatment. DOXO treatment increased mtROS production and reduced mitochondrial mass compared to the vehicle group. Co-treatment with MitoQ decreased mtROS production and preserved mitochondrial mass compared to DOXO alone. MitoQ Co-treatment prevented senescence induction in DOXO-treated HUVECs, evidenced by preventing increased mRNA expression for senescence markers and senescence-associated beta-galactosidase (SA-ꞵgal) activity, alongside higher cell proliferation (BrdU incorporation). Additionally, MitoQ co-treatment reduced DNA damage and telomere dysfunction (DNA damage signaling at telomeres) compared to DOXO alone. Collectively, these data suggest mtROS drives cellular senescence in ECs through increased DNA damage and telomere dysfunction. These findings provide insight into mechanisms underlying DOXO-induced endothelial dysfunction and support mitochondrial-targeted antioxidant treatment as a potential therapeutic to mitigate chemotherapy-induced cardiovascular toxicity.