Simvastatin inhibits L-type Ca 2+ -channel activity through impairment of mitochondrial function

Curry, Liam; Almukhtar, Hani; Alahmed, Jala; Roberts, Richard; Smith, Paul A.

Abstract

Plasma membrane ion channels and mitochondrial electron transport complexes (mETC) are recognised “off-targets” for certain drugs. Simvastatin is one such drug, a lipophilic statin used to treat hypercholesterolaemia, but which is also associated with adverse effects like myopathy and increased risk of glucose intolerance. Such myopathy is thought to arise through adverse actions of simvastatin on skeletal muscle mETC and mitochondrial respiration. In this study we investigated whether the glucose intolerance associated with simvastatin is also mediated via adverse effects on mETC in pancreatic beta-cells since mitochondrial respiration underlies insulin secretion from these cells, an effect in part mediated by promotion of Ca2+ influx via opening of voltage-gated Ca2+ channels (VGCCs). We used murine pancreatic beta-cells to investigate these ideas. Mitochondrial membrane potential, oxygen consumption and ATP-sensitive-K+-channel activity were monitored as markers of mETC activity, respiration and cellular ATP/ADP ratio respectively; Ca2+ channel activity and Ca2+ influx were also measured. In intact beta-cells, simvastatin inhibited oxidative respiration (IC50 ~ 3 µM) and mETC (1< IC50 < 10 µM), effects expected to impair VGCC opening. Consistent with this idea simvastatin > 0.1 µM reversed activation of VGCCs by glucose but had no significant effect in the sugar’s absence. The VGCC effects were mimicked by rotenone which also decreased respiration and ATP/ADP. This study demonstrates modulation of beta-cell VGCC activity by mitochondrial respiration and their sensitivity to mETC inhibitors. This reveals a novel outcome for the action of drugs like simvastatin for which mETC is an “off target”.

Citation

Curry, L., Almukhtar, H., Alahmed, J., Roberts, R., & Smith, P. A. (2019). Simvastatin inhibits L-type Ca 2+ -channel activity through impairment of mitochondrial function. Toxicological Sciences, 169(2), 543–552. https://doi.org/10.1093/toxsci/kfz068

• Journal Article Type: Article
• Acceptance Date: Mar 2, 2019
• Online Publication Date: Mar 11, 2019
• Publication Date: Jun 2, 2019
• Deposit Date: Jan 21, 2020
• Publicly Available Date: Mar 12, 2020
• Journal: Toxicological Sciences
• Print ISSN: 1096-6080
• Electronic ISSN: 1096-0929
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 169
• Issue: 2
• Pages: 543–552
• DOI: https://doi.org/10.1093/toxsci/kfz068
• Public URL: https://nottingham-repository.worktribe.com/output/1602846
• Publisher URL: https://academic.oup.com/toxsci/article-abstract/169/2/543/5374770?redirectedFrom=fulltext
• Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Toxicological Sciences following peer review. The version of record Simvastatin Inhibits L-Type Ca2+-Channel Activity Through Impairment of Mitochondrial Function Liam Curry, Hani Almukhtar, Jala Alahmed, Richard Roberts, Paul A Smith; Toxicological Sciences, Volume 169, Issue 2, June 2019, Pages 543–552, ; is available online at: https://doi.org/10.1093/toxsci/kfz068