Mitochondrial electron transport chain (ETC) targeting shows a great promise in cancer therapy. It is particularly effective in tumors with high ETC activity where ETC-derived reactive oxygen species (ROS) are efficiently induced. Why modern ETC-targeted compounds are tolerated on the organismal level remains unclear. As most somatic cells are in non-proliferative state, the features associated with the ETC in quiescence could account for some of the specificity observed. Here we report that quiescent cells, despite increased utilization of the ETC and enhanced supercomplex assembly, are less susceptible to cell death induced by ETC disruption when glucose is not limiting. Mechanistically, this is mediated by the increased detoxification of ETC-derived ROS by mitochondrial antioxidant defense, principally by the superoxide dismutase 2 - thioredoxin axis. In contrast, under conditions of glucose limitation, cell death is induced preferentially in quiescent cells and is correlated with intracellular ATP depletion but not with ROS. This is related to the inability of quiescent cells to compensate for the lost mitochondrial ATP production by the upregulation of glucose uptake. Hence, elevated ROS, not the loss of mitochondrially-generated ATP, are responsible for cell death induction by ETC disruption in ample nutrients condition, e.g. in well perfused healthy tissues, where antioxidant defense imparts specificity. However, in conditions of limited glucose, e.g. in poorly perfused tumors, ETC disruption causes rapid depletion of cellular ATP, optimizing impact towards tumor-associated dormant cells. In summary, we propose that antioxidant defense in quiescent cells is aided by local glucose limitations to ensure selectivity of ETC inhibition-induced cell death.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Cell Death genetics   MeSH
• Cell Respiration MeSH
• Cell Cycle genetics   MeSH
• Electron Transport Chain Complex Proteins genetics   metabolism   MeSH
• Endothelial Cells cytology   metabolism   MeSH
• Epithelial Cells cytology   metabolism   MeSH
• Gene Expression MeSH
• Glucose metabolism   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Cell Line, Tumor MeSH
• Oxidation-Reduction MeSH
• Reactive Oxygen Species metabolism   MeSH
• Superoxide Dismutase genetics   metabolism   MeSH
• Thioredoxins genetics   metabolism   MeSH
• Cell Line, Transformed MeSH
• Electron Transport MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH