Nicorandil Affects Mitochondrial Respiratory Chain Function by Increasing Complex III Activity and ROS Production in Skeletal Muscle Mitochondria

• Published in: The Journal of membrane biology Vol. 253; no. 4; pp. 309 - 318
• Main Authors: Sánchez-Duarte, E., Cortés-Rojo, C., Sánchez-Briones, L. A., Campos-García, J., Saavedra-Molina, A., Delgado-Enciso, I., López-Lemus, U. A., Montoya-Pérez, R.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2020; Springer Nature B.V
• Subjects: Activation; Adenosine triphosphate; Antioxidants; ATP; Biochemistry; Biomedical and Life Sciences; Channels; Electron transport; Electron transport chain; Flow cytometry; Glycine; Human Physiology; Life Sciences; Lipid peroxidation; Lipids; Mitochondria; Modulators; Muscles; Musculoskeletal system; Potassium; Potassium channels; Reactive oxygen species; Respiration; Skeletal muscle; Spectrophotometry; Thiobarbituric acid; channel; Mitochondria; Reactive oxygen species; Nicorandil; mitoK; Skeletal muscle
• ISSN: 0022-2631; 1432-1424
• DOI: 10.1007/s00232-020-00129-y

Adenosine triphosphate (ATP)-dependent potassium channels openers (K ATP ) protect skeletal muscle against function impairment through the activation of the mitochondrial K ATP channels (mitoK ATP ). Previous reports suggest that modulators of the mitochondrial K ATP channels have additional effects on isolated mitochondria. To determine whether the K ATP  channel opener nicorandil has non-specific effects that explain its protective effect through the mitochondrial function, chicken muscle mitochondria were isolated, and respiration rate was determined pollarographically. The activity of the electron transport chain (ETC) complexes (I–IV) was measured using a spectrophotometric method. Reactive oxygen species (ROS) levels and lipid peroxidation were assessed using flow cytometry and thiobarbituric acid assay, respectively. Both K ATP channel opener nicorandil and K ATP channel blocker 5-hydroxydecanoate (5-HD) decreased mitochondrial respiration; nicorandil increased complex III activity and decreased complex IV activity. The effects of nicorandil on complex III were antagonized by 5-HD. Nicorandil increased ROS levels, effect reverted by either 5-HD or the antioxidant N-2-mercaptopropionyl glycine (MPG). None of these drugs affected lipid peroxidation levels. These findings suggest that K ATP  channel opener nicorandil increases mitochondrial ROS production from complex III. This results by partially blocking electron flow in the complex IV, setting electron carriers in a more reduced state, which is favored by the increase in complex III activity by nicorandil. Overall, our study showed that nicorandil like other mitochondrial K ATP channel openers might not act through mitoK ATP channel activation. Graphic Abstract