Effect of TRO19622 (Olesoxime) on the Functional Activity of Isolated Mitochondria and Cell Viability

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Abstract

TRO19622 (olesoxime), a cholesterol-like cytoprotector, is an experimental drug developed as a potential treatment for a range of incurable degenerative diseases. Recent studies have shown that the main molecular targets of this compound in the cell are porins of the outer mitochondrial membrane, which play a crucial role in regulating the exchange of metabolites between mitochondria and the rest of the cell. Disruption of this channel activity may lead to mitochondrial dysfunction in healthy cells. In this study, key indicators of mitochondrial function and the viability of cells in cultures after incubation with TRO19622 were assessed. It was found that TRO19622 at 15–30 μM concentrations inhibits the coupled and uncoupled respiration rates in isolated mitochondria (state 3 rate and 3UDNP) with succinate as substrate, but does not affect the enzymatic activity of respiratory chain complexes I–IV. It was shown that TRO19622 at the studied doses has no effect on the rate of H2O2 formation in mitochondria and the calcium retention capacity index, which reflects the resistance of the organelles to the calcium-dependent nonspecific pore opening. Incubation of human skin fibroblasts and mammary adenocarcinoma cells (MCF-7) with 30 μM TRO19622 for 48 h has no impact on ROS production and cell viability. How TRO19622 works in the oxidative phosphorylation system and therapeutic prospects for using this mitochondrial-targeted agent are discussed.

About the authors

A. I Ilzorkina

Mari State University; Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences

Yoshkar-Ola, Russia; Pushchino, Russia

N. V Belosludtseva

Mari State University; Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences

Yoshkar-Ola, Russia; Pushchino, Russia

A. A Semenova

Mari State University

Yoshkar-Ola, Russia

M. V Dubinin

Mari State University

Yoshkar-Ola, Russia

K. N Belosludtsev

Mari State University

Email: bekonik@gmail.com
Yoshkar-Ola, Russia

References

  1. Kim J., Gupta R., Blanco L. P., Yang S., ShteinferKuzmine A., Wang K., Zhu J., Yoon H. E., Wang X., Kerkhofs M., Kang H., Brown A. L., Park S.-J., Xu X., Rilland E. Z., Kim M. K., Cohen J. I., Kaplan M. J., Shoshan-Barmatz V., and Chung J. H. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science, 366 (6472), 1531 (2019). doi: 10.1126/science.aav4011
  2. Shoshan-Barmatz V., Maldonado E. N., and Krelin Y. VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress. Cell Stress, 29, 1 (1), 11–36 (2017). doi: 10.15698/cst2017.11.104
  3. Shoshan-Barmatz V. and Golan M. Mitochondrial VDAC1: function in cell life and death and a target for cancer therapy. Curr. Med. Chem., 19 (5), 714 (2012). doi: 10.2174/092986712798992110
  4. Belosludtseva N. V., Dubinin M. V., and Belosludtsev K. N. Pore-forming vdac proteins of the outer mitochondrial membrane: regulation and pathophysiological role. Biochemistry (Moscow), 89 (6), 1061 (2024). doi: 10.1134/S0006297924060075
  5. Varughese J. T., Buchanan S. K., and Pitt A. S. The role of voltage-dependent anion channel in mitochondrial dysfunction and human disease. Cells, 10 (7), 1737 (2021). doi: 10.3390/cells10071737
  6. Ott M., Robertson J. D., Gogvadze V., Zhivotovsky B., and Orrenius S. Cytochrome c release from mitochondria proceeds by a two-step process. Proc. Natl. Acad. Sci. USA, 99 (3), 1259–1263 (2002). doi: 10.1073/pnas.241655498
  7. Tsujimoto Y. and Shimizu S. The voltage-dependent anion channel: an essential player in apoptosis. J. Biochimie, 84 (2–3), 187–193, (2002). doi: 10.1016/s0300-9084(02)01370-6
  8. Yang M., Camara A. K. S., Aldakkak M., et al. Identity and function of a cardiac mitochondrial small conductance Ca2+-activated K+ channel splice variant. Biochim. Biophys. Acta – Bioenergetics, 1858 (6), 442 (2017). doi: 10.1016/j.bbabio.2017.03.005
  9. Tricaud N., Gautier B., Berthelot J., Gonzalez S., and Hameren G. V. Traumatic and diabetic schwann cell demyelination is triggered by a transient mitochondrial calcium release through voltage dependent anion channel 1. Biomedicines, 10 (6), 1447 (2022). doi: 10.3390/biomedicines10061447
  10. Bordet T., Berna P., Abitbol J.-L., and Rebecca M. P. Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals (Basel), 3 (2), 345–368 (2010). doi: 10.3390/ph3020345
  11. Serov D., Tikhonova I., Safronova V., and Astashev M. Calcium activity in response to nAChR ligands in murine bone marrow granulocytes with different Gr-1 expression. J. Cell Biol. Int., 45 (7), 1533–1545 (2021). doi: 10.1002/cbin.11593
  12. Dubinin M. V., Nedopekina D. A., Ilzorkina A. I., Semenova A. A., Sharapov V. A., Davletshin E. V., Mikina N. V., Belsky Y. P., Spivak A. Yu., Akatov V. S., Belosludtseva N. V., Jiankang L., and Belosludtsev K. N. Conjugation of triterpenic acids of ursane and oleanane types with mitochondria-targeting cation F16 synergistically enhanced their cytotoxicity against tumor cells. Membranes, 13 (6), 563 (2023). doi: 10.3390/membranes13060563
  13. Belosludtsev K. N., Belosludtseva N. V., Kosareva E. A., Talanov E. Y., Gudkov S. V., and Dubinin M. V. Itaconic acid impairs the mitochondrial function by the inhibition of complexes II and IV and induction of the permeability transition pore opening in rat liver mitochondria. Biochimie, 176, 150–157 (2020). doi: 10.1016/j.biochi.2020.07.011
  14. Belosludtseva N. V., Starinets V. S., Semenova A. A., Igoshkina A. D., Dubinin M. V., and Belosludtsev K. N. S-15176 Difumarate salt can impair mitochondrial function through inhibition of the respiratory complex III and permeabilization of the inner mitochondrial membrane. Biology (Basel), 11 (3), 380 (2022). doi: 10.3390/biology11030380
  15. Dubinin M. V., Semenova A. A., Nedopekina D. A., Davletshin E. V., Spivak A. Y., and Belosludtsev K. N. Mitochondrial dysfunction induced by F16-betulin conjugate and its role in cell death initiation. Membranes, 11 (5), 352 (2021). doi: 10.3390/membranes11050352
  16. Spinazzi M., Casarin A., Pertegato V., Salviati L., Angelini C. Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nature Protoc., 7 (6), 1235–1246 (2012). doi: 10.1038/nprot.2012.058
  17. Belosludtsev K. N., Dubinin M. V., Talanov E. Yu., Starinets V. S., Tenkov K. S., Zakharova N. M., and Belosludtseva N. V. Transport of Ca2+ and Ca2+-dependent permeability transition in the liver and heart mitochondria of rats with different tolerance to acute hypoxia. Biomolecules, 10 (1), 114 (2020). doi: 10.3390/biom10010114
  18. Verma A., Shteinfer-Kuzmine A., Kamenetsky N., Pittala S., Paul A., Crystal E. N., Ouro A., ChalifaCaspi V., Pandey S. K., Monsonego A., Vardi N., Knafo S., and Shoshan-Barmatz V. Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology. Transl. Neurodegener., 11 (1), 58 (2022). doi: 10.1186/s40035-022-00329-7
  19. Mookerjee S. A., Gerencser A. A., Watson M. A., and Brand M. D. Controlled power: how biology manages succinate-driven energy release. Biochem. Soc. Trans., 49 (6), 2929–2939 (2021). doi: 10.1042/BST20211032
  20. Martin J. L., Costa A. S. H., Gruszczyk A. V., BeachT. E., Allen F. M., Prag H. A., Hinchy E. C., Mahbubani K., Hamed M., Tronci L., Nikitopoulou E., James A. M., Krieg T., Robinson A. J., HuangM. M., Caldwell S. T., Logan A., Pala L., Hartley R. C., Frezza Ch. , Saeb-Parsy K., and Murphy M. P. Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation. Nature Metab., 1, 966–974 (2019). doi: 10.1038/s42255-019-0115-y
  21. Chouchani E. T., Pell V. R., Gaude E., Aksentijević D., Sundier S. Y., Robb E. L., Logan A., Nadtochiy S. M., Ord E. N. J., Smith A. C., Eyassu F., Shirley R., Hu Ch.-H., Dare A. J., James A. M., Rogatti S., Hartley R. C., Eaton S., Costa A. S. H., Brookes P. S., Davidson S. M., Duchen M. R., Saeb-Parsy K., Shattock M. J., Robinson A. J., Work L. M., Frezza Ch., Krieg T., and Murphy M. P. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature, 515 (7527), 431–435 (2014). doi: 10.1038/nature13909
  22. Bordet T., Buisson B., Michaud M., Drouot C., Galea P., Delaage P., Akentieva N. P., Evers A. S., Covey D. F., Ostuni M. A., Lacapere J. J., Massaad C., Schumacher M., Steidl E. M., Maux D., Delaage M., Henderson C. E., and Pruss R. M. Identification and characterization of cholest-4-en-3-one,oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J. Pharmacol. Exp. Ther., 322 (2), 709–720 (2007). doi: 10.1124/jpet.107.123000
  23. Muntoni F., Bertini E., Comi G., Kirschner J., Lusakowska A., Mercuri E., Scoto M., Ludo van der Pol W., Vuillerot C., Burdeska A., El-Khairi M., Fontoura P., Ives J., Gorni K., Reid C., and Fuerst-Recktenwald S. Long-term follow-up of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial. Neuromusc. Disorders, 30 (12), 959–969 (2020). doi: 10.1016/j.nmd.2020.10.008

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