Mitochondrial Glutamine Metabolism Determines Senescence Induction After Chemotherapy

Cellular senescence is an important tumor-suppressive mechanism that arrests the cell cycle of damaged cells after diverse stresses. This study aimed to elucidate the role of mitochondrial glutamine (Gln) metabolism in senescence cell-fate decision after DNA damage.

β-galactosidase staining was used to determine senescence induction. The mechanistic target of rapamycin (mTOR) activity and p21 expression were examined by western blot. Cell proliferation and clonogenic growth were evaluated.

Inhibition of mitochondrial Gln metabolism suppressed DNA damage-induced senescence, whereas increased Gln anaplerosis resulted in a profound induction of senescence. Mechanistically, Gln anaplerosis mediated senescence induction by activating mTOR signaling upon DNA damage. Importantly, enhancing Gln anaplerosis could reduce the emergence of proliferative subpopulations of cancer cells after exposure to non-lethal doses of chemotherapeutic agents.

Mitochondrial Gln metabolism is an important regulator of DNA damage-induced senescence, which may be used for developing effective therapeutic approaches.