Selective elimination of senescent cells by mitochondrial targeting is regulated via ANT2

Cellular senescence is stable cell cycle arrest limiting proliferative potential of cells. Inability of immune cells to eliminate senescent cells from the organism may lead to development of age-related diseases. We have developed several mitocans, mitochondrially targeted agents inducing apoptosis of cancer cells, whose mitochondrial uptake is driven by high mitochondrial potential of those cells. This efficacy of mitocans to target cells with increased mitochondrial potential, such as senescent cells, makes them candidates for senolytic agents. Mitochondrial targeted tamoxifen (MitoTam), unlike other anti-cancer agents, not only kills cancer cells without inducing senescence, but also selectively eliminates both malignant and non-cancerous senescent cells. In naturally aged mice, MitoTam treatment resulted in decrease of senescent markers in all tested organs. We found a role of adenine nucleotide translocator 2 (ANT2) in the survival of MitoTam-treated cells. Restoration of ANT2 in senescent cells caused resistance to MitoTam, while its downregulation in control cells promoted MitoTam-induced elimination. The ability of MitoTam to eliminate senescent cells results in new strategy for treatment of age-related pathologies and senescence-associated inflammation or tumorigenesis.