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

Sona Hubackova*, Eliska Davidova, Katerina Rohlenova, Jan Stursa, Lukas Werner, Ladislav Andera, Lan Feng Dong, Mikkel G. Terp, Zdenek Hodny, Henrik J. Ditzel, Jakub Rohlena, Jiri Neuzil

*Corresponding author for this work

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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.

Original languageEnglish
JournalCell Death and Differentiation
Volume26
Issue number2
Pages (from-to)276–290
ISSN1350-9047
DOIs
Publication statusPublished - 1. Feb 2019

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Cell Aging
Cell Cycle Checkpoints
Neoplasms
Down-Regulation
Pathology
In Vitro Techniques

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Hubackova, S., Davidova, E., Rohlenova, K., Stursa, J., Werner, L., Andera, L., ... Neuzil, J. (2019). Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death and Differentiation, 26(2), 276–290. https://doi.org/10.1038/s41418-018-0118-3
Hubackova, Sona ; Davidova, Eliska ; Rohlenova, Katerina ; Stursa, Jan ; Werner, Lukas ; Andera, Ladislav ; Dong, Lan Feng ; Terp, Mikkel G. ; Hodny, Zdenek ; Ditzel, Henrik J. ; Rohlena, Jakub ; Neuzil, Jiri. / Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. In: Cell Death and Differentiation. 2019 ; Vol. 26, No. 2. pp. 276–290.
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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.",
author = "Sona Hubackova and Eliska Davidova and Katerina Rohlenova and Jan Stursa and Lukas Werner and Ladislav Andera and Dong, {Lan Feng} and Terp, {Mikkel G.} and Zdenek Hodny and Ditzel, {Henrik J.} and Jakub Rohlena and Jiri Neuzil",
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Hubackova, S, Davidova, E, Rohlenova, K, Stursa, J, Werner, L, Andera, L, Dong, LF, Terp, MG, Hodny, Z, Ditzel, HJ, Rohlena, J & Neuzil, J 2019, 'Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2', Cell Death and Differentiation, vol. 26, no. 2, pp. 276–290. https://doi.org/10.1038/s41418-018-0118-3

Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. / Hubackova, Sona; Davidova, Eliska; Rohlenova, Katerina; Stursa, Jan; Werner, Lukas; Andera, Ladislav; Dong, Lan Feng; Terp, Mikkel G.; Hodny, Zdenek; Ditzel, Henrik J.; Rohlena, Jakub; Neuzil, Jiri.

In: Cell Death and Differentiation, Vol. 26, No. 2, 01.02.2019, p. 276–290.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2

AU - Hubackova, Sona

AU - Davidova, Eliska

AU - Rohlenova, Katerina

AU - Stursa, Jan

AU - Werner, Lukas

AU - Andera, Ladislav

AU - Dong, Lan Feng

AU - Terp, Mikkel G.

AU - Hodny, Zdenek

AU - Ditzel, Henrik J.

AU - Rohlena, Jakub

AU - Neuzil, Jiri

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41418-018-0118-3

M3 - Journal article

C2 - 29786070

AN - SCOPUS:85047204527

VL - 26

SP - 276

EP - 290

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 2

ER -

Hubackova S, Davidova E, Rohlenova K, Stursa J, Werner L, Andera L et al. Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death and Differentiation. 2019 Feb 1;26(2):276–290. https://doi.org/10.1038/s41418-018-0118-3