Resistance of mitochondrial DNA-depleted cells against cell death: Role of mitochondrial superoxide dismutase

We have shown that mitochondrial DNA-depleted (ρ⁰) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of ρ⁰ cells. We studied the changes of gene expression in SK-Hep1 ρ⁰ cells. DNA chip analysis showed that MnSOD expression was profoundly increased in ρ⁰ cells. O₂^.- contents increased during ρ⁰ cell derivation but became normalized after establishment of ρ⁰ phenotypes, suggesting that MnSOD induction is an adaptive process to increased 0₂^.-. ρ⁰ cells were resistant to menadione, paraquat, or doxorubicin, and O₂ ^.- contents after treatment with them were lower in ρ ⁰ cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in ρ⁰ cells, rendering them resistant to exogenous H ₂O₂. ρ⁰ cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of ρ⁰ cells also showed increased A1n801) expression and resistance against ROS. Heme oxygenase-1 expression was increased in ρ⁰ cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in ρ⁰ cells and their resistance against ROS donors. These results indicate that ρ⁰ cells are resistant to cell death contrary to previous reports and suggest that an adaptive increase in the expression of antioxidant enzymes renders cancer cells or aged cells with frequent mitochondrial DNA mutations to resist against oxidative stress, host anti-cancer surveillance, or chemotherapeutic agents, conferring survival advantage on them.