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 can induce 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, mitoquinol (MitoQ); however, its precise protective mechanism in endothelial cells (ECs) remains unclear. The present study hypothesizes that cotreating 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 h after DOXO and/or MitoQ treatment. DOXO treatment increased mtROS production and reduced mitochondrial mass compared with the vehicle group. Cotreatment with MitoQ decreased mtROS production and preserved mitochondrial mass compared with DOXO alone. MitoQ Cotreatment prevented senescence induction in DOXO-treated HUVECs, evidenced by preventing increased mRNA expression for senescence markers and senescence-associated β-galactosidase activity, alongside higher cell proliferation (bromodeoxyuridine incorporation). In addition, MitoQ cotreatment reduced DNA damage and telomere dysfunction (DNA damage signaling at telomeres) compared with 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.