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

Abstract

TRO19622 (olesoxime, a cholesterol-like cytoprotector) is an experimental drug developed for the potential therapy of a number of incurable degenerative diseases. The main molecular target of this compound in the cell is the porin proteins of the outer mitochondrial membrane, which play a key role in regulating the exchange of metabolites between mitochondria and the rest of the cell. Violations of the activity of these channels can cause the development of mitochondrial dysfunction in healthy cells. This paper evaluates the main indicators of mitochondrial functions and the cell viability index in cultures after their incubation with TRO19622. It was found that TRO19622 at concentrations of 15–30 μM inhibited the rates of phosphorylating and uncoupled respiration of isolated mitochondria (states 3 and 3UDNP) with succinate as a substrate, but did not affect the enzymatic activity of complexes I–IV of the respiratory chain. It was shown that TRO19622 in the studied doses did not affect the rate of H₂O₂ formation in mitochondria and the parameter of calcium capacity, reflecting the resistance of organelles to the opening of a calcium-dependent nonspecific pore. Incubation of human skin fibroblasts and breast adenocarcinoma cells (MCF-7) with 30 μM TRO19622 for 48 h had no effect on the production of reactive oxygen species and cell viability. The mechanisms of action of TRO19622 on the oxidative phosphorylation system and the prospects of using this mitochondrial-directed therapeutic agent are discussed.