Alisporivir Normalizes Mitochondrial Function of Primary Mouse Lung Endothelial Cells Under Conditions of Hyperglycemia

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Vlada S. Starinets^1,2, Dmitriy A. Serov^3,4, Nikita V. Penkov⁴, Natalia V. Belosludtseva^1,2, Mikhail V. Dubinin¹, and Konstantin N. Belosludtsev^1,2,a*

¹Mari State University, 424001 Yoshkar-Ola, Mari El, Russia

²Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

³Biophotonics Center, Prokhorov General Physics Institute, Russian Academy of Sciences, 119991 Moscow, Russia

⁴Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

^* To whom correspondence should be addressed.

Received April 11, 2022; Revised May 16, 2022; Accepted June 6, 2022

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Effect of alisporivir (a mitochondrial permeability transition pore inhibitor) on the development of mitochondrial dysfunction under hyperglycemic conditions in the primary culture of mouse lung endothelial cells was investigated in this work. We demonstrated that hyperglycemia (30 mM glucose for 24 h) leads to the decrease in viability of the pulmonary endotheliocytes, causes mitochondrial dysfunction manifested by the drop in membrane potential and increase in superoxide anion generation as well as facilitates opening of the mitochondrial permeability transition pore (MPT pore). Incubation of endothelial cells with 5 µM alisporivir under hyperglycemic conditions leads to the increase in cell viability, restoration of the membrane potential level and of the MPT pore opening activity to control values. Hyperglycemia causes increased mitophagy in the lung endothelial cells: we observed increase in the degree of colocalization of mitochondria and lysosomes and upregulation of the Parkin gene expression. Alisporivir restores these parameters back to the levels observed in the control cells. Hyperglycemia results in the increase in the expression of the Drp1 gene in endotheliocytes responsible for synthesis of the protein involved in the process of mitochondria fission. Alisporivir does not significantly alter expression of the genes. The paper discusses mechanisms of the effect of alisporivir on mitochondrial dysfunction in murine pulmonary endotheliocytes under conditions of hyperglycemia.

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KEY WORDS: mitochondria, alisporivir, mitochondrial permeability transition pore, hyperglycemia, diabetes mellitus, mitophagy

DOI: 10.1134/S0006297922070033

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