Bcl-xL interaction with VDAC1 reduces mitochondrial Ca2+ uptake, allowing the establishment of Therapy-Induced Senescence.

Abstract

Cellular senescence, a state of irreversible growth arrest, is characterized by various phenotypic changes, including altered mitochondrial function. While the role of mitochondria in senescence is well-established, the mechanisms underlying their involvement remain unclear. Here, we investigate the early stages of therapy-induced senescence (TIS) and identify a novel anti-apoptotic mechanism mediated by Bcl-xL and VDAC1, two key regulators of mitochondrial calcium (Ca2+) homeostasis. We find that Bcl-xL expression increases in early TIS cells and localizes to the mitochondria, where it interacts with the voltage-dependent anion channel 1 (VDAC1). This interaction dampens mitochondrial Ca2+ uptake, thereby preventing Ca2+ overload and apoptosis. Disrupting this interaction using the BH3 mimetic ABT-263 or Bcl-xL targeting siRNA increases mitochondrial Ca2+ uptake, leading to apoptosis and blocking the formation of senescent cells. These findings uncover a previously unrecognized role of the Bcl-xL VDAC1 axis in regulating mitochondrial Ca2+ dynamics during the onset of senescence. Our work provides mechanistic insight into how senescent cells evade apoptosis, highlighting potential therapeutic targets for selectively eliminating them in cancer and age-related diseases.