Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2
Sona Hubackova1, Eliska Davidova2, Katerina Rohlenova2,3
1Laboratory of Molecular Therapy, Institute of Biotechnology, Czech Academy of Sciences, Prague, 252 50, Czech Republic. sona.hubackova@ibt.cas.cz.
Abstract:
Cellular senescence is a form of cell cycle arrest that limits the proliferative potential of cells, including tumour cells. However, inability of immune cells to subsequently eliminate senescent cells from the organism may lead to tissue damage, inflammation, enhanced carcinogenesis and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role for an anticancer agent targeting mitochondria, that may result in a new strategy for the treatment of age-related diseases and senescence-associated pathologies.
Insights
Mitochondria-targeted tamoxifen (MitoTam) eliminates senescent cells, unlike conventional drugs. This novel anticancer agent offers a potential strategy for treating age-related diseases and senescence-associated pathologies by targeting adenine nucleotide translocase-2 (ANT2) expression.
Area of Science:
- Cellular biology
- Aging research
- Oncology
Background:
- Cellular senescence is a state of irreversible cell cycle arrest.
- Accumulation of senescent cells contributes to tissue damage, inflammation, and age-related diseases.
- Current anticancer therapies may induce senescence, complicating treatment outcomes.
Purpose of the Study:
- To investigate the effects of mitochondria-targeted tamoxifen (MitoTam) on senescent cells.
- To explore the potential of MitoTam as a therapeutic agent for senescence-associated conditions.
- To elucidate the mechanism underlying senescent cell susceptibility to MitoTam.
Main Methods:
- In vitro and in vivo experiments using cancer cells and aged mice.
- Treatment with MitoTam and conventional anticancer agents.
- Analysis of senescence markers and adenine nucleotide translocase-2 (ANT2) expression.
- Genetic manipulation of ANT2 levels in senescent and non-senescent cells.
Main Results:
- MitoTam eliminates cancer cells without inducing senescence.
- MitoTam selectively eliminates both malignant and non-cancerous senescent cells.
- A significant decrease in senescence markers was observed in aged mice treated with MitoTam.
- Senescent cells' susceptibility to MitoTam is linked to low ANT2 expression.
Conclusions:
- MitoTam presents a novel therapeutic strategy for eliminating senescent cells.
- Targeting mitochondrial pathways offers a new approach for treating age-related diseases and senescence-associated pathologies.
- ANT2 expression levels are critical in determining senescent cell sensitivity to MitoTam.
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