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.

Abstract

Itaconic acid (methylene-succinic acid, ItA) is an unsaturated dicarboxylic acid that is secreted by mammalian macrophages in response to a pro-inflammatory stimulus and shows an anti-inflammatory/antibacterial effect. Being a mitochondrial metabolite, it exhibits an inhibitory activity on succinate dehydrogenase and subsequently induces mitochondrial dysfunction. The present study has shown that ItA dose-dependently inhibited ADP- and DNP-stimulated (uncoupled) respiration of rat liver mitochondria energized with succinate. This effect of ItA could be related to the suppression of the activity of complex II and the combined activity of complexes II + III of the respiratory chain. At the same time, ItA had no effect on the activity of the dicarboxylate carrier, which catalyzes the transport of succinate across the inner mitochondrial membrane. It was found that 4 mM ItA diminished the rates of ADP- and DNP-stimulated mitochondrial respiration supported by the substrates of complex I glutamate and malate. A study of the effect of ItA on the activity of complexes of the respiratory chain showed that it decreases the activity of complex IV. It was observed that 4 mM ItA inhibited the rate of H2O2 production by mitochondria. At the same time, ItA promoted the opening of the cyclosporin A-sensitive Ca2+-dependent permeability transition pore. The latter was revealed as the decrease in the calcium retention capacity of mitochondria and the stimulation of release of cytochrome c from the organelles. ItA by itself promoted the cytochrome c release from mitochondria. Possible mechanisms of the effect of ItA on mitochondrial function are discussed.

• Authors: Konstantin N Belosludtsev, Natalia V Belosludtseva, Ekaterina A Kosareva, Eugeny Yu Talanov, Sergey V Gudkov, Mikhail V Dubinin
• Journal: Biochimie (Biochimie) Vol. 176 Pg. 150-157 (Sep 2020) ISSN: 1638-6183 [Electronic] France
• PMID: 32721502 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Chemical References

• Mitochondrial Permeability Transition Pore
• Succinates
• Cytochromes c
• Electron Transport Complex II
• Electron Transport Complex IV
• itaconic acid
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cytochromes c (metabolism)
• Electron Transport Complex II (antagonists & inhibitors, metabolism)
• Electron Transport Complex IV (antagonists & inhibitors, metabolism)
• Male
• Mitochondria, Liver (metabolism)
• Mitochondrial Permeability Transition Pore (antagonists & inhibitors, metabolism)
• Rats
• Rats, Wistar
• Succinates (pharmacology)