Abstract
Mitochondria and oxidative phosphorylation (OXPHOS) are emerging as intriguing targets for the efficient elimination of cancer cells. The specificity of this approach is aided by the capacity of non-proliferating non-cancerous cells to withstand oxidative insult induced by OXPHOS inhibition. Recently we discovered that mitochondrial targeting can also be employed to eliminate senescent cells, where it breaks the interplay between OXPHOS and ATP transporters that appear important for the maintenance of mitochondrial morphology and viability in the senescent setting. Hence, mitochondria/OXPHOS directed pharmacological interventions show promise in several clinically-relevant scenarios that call for selective removal of cancer and senescent cells.
Acknowledgments
The authors’ work is in part supported by grants from the Czech Science Foundation 17-20904S and 16-22823S to J.R., 18-02550S and 17-07635S to S.H. and 17-01192J and 16-12719S to J.N., the institutional support of the Institute of Biotechnology, RVO: 86652036 and by the BIOCEV European Regional Development Fund CZ.1.05/1.100.
References
Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., and van Deursen, J.M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236.10.1038/nature10600Search in Google Scholar PubMed PubMed Central
Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., Saltness, R.A., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., et al. (2016). Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189.10.1038/nature16932Search in Google Scholar PubMed PubMed Central
Barath, P., Luciakova, K., Hodny, Z., Li, R., and Nelson, B.D. (1999). The growth-dependent expression of the adenine nucleotide translocase-2 (ANT2) gene is regulated at the level of transcription and is a marker of cell proliferation. Exp. Cell Res. 248, 583–588.10.1006/excr.1999.4432Search in Google Scholar PubMed
Beausejour, C.M., Krtolica, A., Galimi, F., Narita, M., Lowe, S.W., Yaswen, P., and Campisi, J. (2003). Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222.10.1093/emboj/cdg417Search in Google Scholar PubMed PubMed Central
Berry, D.C., Jiang, Y., Arpke, R.W., Close, E.L., Uchida, A., Reading, D., Berglund, E.D., Kyba, M., and Graff, J.M. (2017). Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab. 25, 166–181.10.1016/j.cmet.2016.10.023Search in Google Scholar PubMed PubMed Central
Blecha, J., Novais, S.M., Rohlenova, K., Novotna, E., Lettlova, S., Schmitt, S., Zischka, H., Neuzil, J., and Rohlena, J. (2017). Antioxidant defense in quiescent cells determines selectivity of electron transport chain inhibition-induced cell death. Free Radic. Biol. Med. 112, 253–266.10.1016/j.freeradbiomed.2017.07.033Search in Google Scholar PubMed
Chae, Y.K., Arya, A., Malecek, M.K., Shin, D.S., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Altman, J.K., Platanias, L., et al. (2016). Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780.10.18632/oncotarget.8194Search in Google Scholar PubMed PubMed Central
Chang, J., Wang, Y., Shao, L., Laberge, R.M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N.E., Ding, S., Feng, W., et al. (2016). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83.10.1038/nm.4010Search in Google Scholar PubMed PubMed Central
Chevrollier, A., Loiseau, D., Reynier, P., and Stepien, G. (2011). Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism. Biochim. Biophys. Acta 1807, 562–567.10.1016/j.bbabio.2010.10.008Search in Google Scholar PubMed
Demaria, M., O’Leary, M.N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A.M., et al. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176.10.1158/2159-8290.CD-16-0241Search in Google Scholar PubMed PubMed Central
Dorr, J.R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Dabritz, J.H., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., et al. (2013). Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425.10.1038/nature12437Search in Google Scholar PubMed
Eggert, T., Wolter, K., Ji, J., Ma, C., Yevsa, T., Klotz, S., Medina-Echeverz, J., Longerich, T., Forgues, M., Reisinger, F., et al. (2016). Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547.10.1016/j.ccell.2016.09.003Search in Google Scholar PubMed PubMed Central
Ellinghaus, P., Heisler, I., Unterschemmann, K., Haerter, M., Beck, H., Greschat, S., Ehrmann, A., Summer, H., Flamme, I., Oehme, F., et al. (2013). BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med. 2, 611–624.10.1002/cam4.112Search in Google Scholar PubMed PubMed Central
Garcia-Bermudez, J., Baudrier, L., La, K., Zhu, X.G., Fidelin, J., Sviderskiy, V.O., Papagiannakopoulos, T., Molina, H., Snuderl, M., Lewis, C.A., et al. (2018). Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat. Cell Biol. 20, 775–781.10.1038/s41556-018-0118-zSearch in Google Scholar PubMed PubMed Central
Gregoire, M., Morais, R., Quilliam, M.A., and Gravel, D. (1984). On auxotrophy for pyrimidines of respiration-deficient chick embryo cells. Eur. J. Biochem. 142, 49–55.10.1111/j.1432-1033.1984.tb08249.xSearch in Google Scholar PubMed
Gui, D.Y., Sullivan, L.B., Luengo, A., Hosios, A.M., Bush, L.N., Gitego, N., Davidson, S.M., Freinkman, E., Thomas, C.J., and Vander Heiden, M.G. (2016). Environment dictates dependence on mitochondrial complex I for NAD+ and aspartate production and determines cancer cell sensitivity to metformin. Cell Metab. 24, 716–727.10.1016/j.cmet.2016.09.006Search in Google Scholar PubMed PubMed Central
Hubackova, S., Kucerova, A., Michlits, G., Kyjacova, L., Reinis, M., Korolov, O., Bartek, J., and Hodny, Z. (2016). IFNg induces oxidative stress, DNA damage and tumor cell senescence via TGFb/SMAD signaling-dependent induction of Nox4 and suppression of ANT2. Oncogene 35, 1236–1249.10.1038/onc.2015.162Search in Google Scholar PubMed
Hubackova, S., Davidova, E., Rohlenova, K., Stursa, J., Werner, L., Andera, L., Dong, L., Terp, M.G., Hodny, Z., Ditzel, H.J., et al. (2018). Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death Differ. 1–15. DOI: 10.1038/s41418-018-0118-3.10.1038/s41418-018-0118-3Search in Google Scholar PubMed PubMed Central
Hutter, E., Renner, K., Pfister, G., Stockl, P., Jansen-Durr, P., and Gnaiger, E. (2004). Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem. J. 380, 919–928.10.1042/bj20040095Search in Google Scholar PubMed PubMed Central
Jang, J.Y., Choi, Y., Jeon, Y.K., and Kim, C.W. (2008). Suppression of adenine nucleotide translocase-2 by vector-based siRNA in human breast cancer cells induces apoptosis and inhibits tumor growth in vitro and in vivo. Breast Cancer Res. 10, R11.10.1186/bcr1857Search in Google Scholar PubMed PubMed Central
Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551.10.1038/nature10599Search in Google Scholar PubMed
Kaplon, J., Zheng, L., Meissl, K., Chaneton, B., Selivanov, V.A., Mackay, G., van der Burg, S.H., Verdegaal, E.M., Cascante, M., Shlomi, T., et al. (2013). A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112.10.1038/nature12154Search in Google Scholar PubMed
Kluckova, K., Sticha, M., Cerny, J., Mracek, T., Dong, L., Drahota, Z., Gottlieb, E., Neuzil, J., and Rohlena, J. (2015). Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation. Cell Death Dis. 6, e1749.10.1038/cddis.2015.110Search in Google Scholar PubMed PubMed Central
Kretova, M., Sabova, L., Hodny, Z., Bartek, J., Kollarovic, G., Nelson, B.D., Hubackova, S., and Luciakova, K. (2014). TGF-b/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence. Cell. Signal. 26, 2903–2911.10.1016/j.cellsig.2014.08.029Search in Google Scholar PubMed
Lemons, J.M., Feng, X.J., Bennett, B.D., Legesse-Miller, A., Johnson, E.L., Raitman, I., Pollina, E.A., Rabitz, H.A., Rabinowitz, J.D., and Coller, H.A. (2010). Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 8, e1000514.10.1371/journal.pbio.1000514Search in Google Scholar PubMed PubMed Central
Levy, S.E., Chen, Y.S., Graham, B.H., and Wallace, D.C. (2000). Expression and sequence analysis of the mouse adenine nucleotide translocase 1 and 2 genes. Gene 254, 57–66.10.1016/S0378-1119(00)00252-3Search in Google Scholar PubMed
Loffler, M. (1980). On the role of dihydroorotate dehydrogenase in growth cessation of Ehrlich ascites tumor cells cultured under oxygen deficiency. Eur. J. Biochem. 107, 207–215.10.1111/j.1432-1033.1980.tb04641.xSearch in Google Scholar PubMed
Loffler, M., Fairbanks, L.D., Zameitat, E., Marinaki, A.M., and Simmonds, H.A. (2005). Pyrimidine pathways in health and disease. Trends Mol. Med. 11, 430–437.10.1016/j.molmed.2005.07.003Search in Google Scholar PubMed
Milanovic, M., Fan, D.N.Y., Belenki, D., Dabritz, J.H.M., Zhao, Z., Yu, Y., Dorr, J.R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I.A., et al. (2018). Senescence-associated reprogramming promotes cancer stemness. Nature 553, 96–100.10.1038/nature25167Search in Google Scholar PubMed
Minamino, T., Orimo, M., Shimizu, I., Kunieda, T., Yokoyama, M., Ito, T., Nojima, A., Nabetani, A., Oike, Y., Matsubara, H., et al. (2009). A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087.10.1038/nm.2014Search in Google Scholar PubMed
Missios, P., Zhou, Y., Guachalla, L.M., von Figura, G., Wegner, A., Chakkarappan, S.R., Binz, T., Gompf, A., Hartleben, G., Burkhalter, M.D., et al. (2014). Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice. Nat. Commun. 5, 4924.10.1038/ncomms5924Search in Google Scholar PubMed PubMed Central
Molina, J.R., Sun, Y., Protopopova, M., Gera, S., Bandi, M., Bristow, C., McAfoos, T., Morlacchi, P., Ackroyd, J., Agip, A.A., et al. (2018). An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 24, 1036–1046.10.1038/s41591-018-0052-4Search in Google Scholar PubMed
Munoz-Espin, D. and Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496.10.1038/nrm3823Search in Google Scholar PubMed
Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C.L., Lahat, A., Day, C.P., Burt, A., Palmer, A., Anstee, Q.M., et al. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691.10.1038/ncomms15691Search in Google Scholar PubMed PubMed Central
Palikaras, K. and Tavernarakis, N. (2014). Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp. Gerontol. 56, 182–188.10.1016/j.exger.2014.01.021Search in Google Scholar PubMed
Rohlenova, K., Sachaphibulkij, K., Stursa, J., Bezawork-Geleta, A., Blecha, J., Endaya, B., Werner, L., Cerny, J., Zobalova, R., Goodwin, J., et al. (2017). Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2(high) breast cancer. Antioxid. Redox Signal. 26, 84–103.10.1089/ars.2016.6677Search in Google Scholar PubMed PubMed Central
Sabin, R.J. and Anderson, R.M. (2011). Cellular senescence – its role in cancer and the response to ionizing radiation. Genome Integr. 2, 7.10.1186/2041-9414-2-7Search in Google Scholar PubMed PubMed Central
Sage, J., Miller, A.L., Perez-Mancera, P.A., Wysocki, J.M., and Jacks, T. (2003). Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228.10.1038/nature01764Search in Google Scholar PubMed
Schonfeld, P., Schild, L., and Bohnensack, R. (1996). Expression of the ADP/ATP carrier and expansion of the mitochondrial (ATP+ADP) pool contribute to postnatal maturation of the rat heart. Eur. J. Biochem. 241, 895–900.10.1111/j.1432-1033.1996.00895.xSearch in Google Scholar PubMed
Sciacovelli, M., Gonçalves, E., Johnson, T.I., Zecchini, V.R., da Costa, A.S.H., Gaude, E., Drubbel, A.V., Theobald, S.J., Abbo, S.R., Tran, M.G.B., et al. (2016). Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547.10.1038/nature19353Search in Google Scholar PubMed PubMed Central
Senkowski, W., Zhang, X., Olofsson, M.H., Isacson, R., Hoglund, U., Gustafsson, M., Nygren, P., Linder, S., Larsson, R., and Fryknas, M. (2015). Three-dimensional cell culture-based screening identifies the anthelmintic drug nitazoxanide as a candidate for treatment of colorectal cancer. Mol. Cancer Ther. 14, 1504–1516.10.1158/1535-7163.MCT-14-0792Search in Google Scholar PubMed
Sone, H. and Kagawa, Y. (2005). Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48, 58–67.10.1007/s00125-004-1605-2Search in Google Scholar PubMed
St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J.M., Rhee, J., Jager, S., Handschin, C., Zheng, K., Lin, J., Yang, W., et al. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397–408.10.1016/j.cell.2006.09.024Search in Google Scholar PubMed
Sullivan, L.B., Gui, D.Y., Hosios, A.M., Bush, L.N., Freinkman, E., and Vander Heiden, M.G. (2015). Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552–563.10.1016/j.cell.2015.07.017Search in Google Scholar PubMed PubMed Central
Sullivan, L.B., Luengo, A., Danai, L.V., Bush, L.N., Diehl, F.F., Hosios, A.M., Lau, A.N., Elmiligy, S., Malstrom, S., Lewis, C.A., et al. (2018). Aspartate is an endogenous metabolic limitation for tumour growth. Nat. Cell Biol. 20, 782–788.10.1038/s41556-018-0125-0Search in Google Scholar PubMed PubMed Central
Tan, A.S., Baty, J.W., Dong, L.F., Bezawork-Geleta, A., Endaya, B., Goodwin, J., Bajzikova, M., Kovarova, J., Peterka, M., Yan, B., et al. (2015). Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 21, 81–94.10.1016/j.cmet.2014.12.003Search in Google Scholar PubMed
Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033.10.1126/science.1160809Search in Google Scholar PubMed PubMed Central
Viale, A., Pettazzoni, P., Lyssiotis, C.A., Ying, H., Sanchez, N., Marchesini, M., Carugo, A., Green, T., Seth, S., Giuliani, V., et al. (2014). Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632.10.1038/nature13611Search in Google Scholar PubMed PubMed Central
Weinberg, F., Hamanaka, R., Wheaton, W.W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G.M., Budinger, G.R., and Chandel, N.S. (2010). Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. USA 107, 8788–8793.10.1073/pnas.1003428107Search in Google Scholar PubMed PubMed Central
Xu, M., Pirtskhalava, T., Farr, J.N., Weigand, B.M., Palmer, A.K., Weivoda, M.M., Inman, C.L., Ogrodnik, M.B., Hachfeld, C.M., Fraser, D.G., et al. (2018). Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256.10.1038/s41591-018-0092-9Search in Google Scholar PubMed PubMed Central
Yan, B., Stantic, M., Zobalova, R., Bezawork-Geleta, A., Stapelberg, M., Stursa, J., Prokopova, K., Dong, L., and Neuzil, J. (2015). Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner. BMC Cancer 15, 401.10.1186/s12885-015-1394-7Search in Google Scholar PubMed PubMed Central
Zielonka, J., Joseph, J., Sikora, A., Hardy, M., Ouari, O., Vasquez-Vivar, J., Cheng, G., Lopez, M., and Kalyanaraman, B. (2017). Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem. Rev. 117, 10043–10120.10.1021/acs.chemrev.7b00042Search in Google Scholar PubMed PubMed Central
©2019 Walter de Gruyter GmbH, Berlin/Boston