Effects of statins on mitochondrial pathways

Abstract

Statins are a family of drugs that are used for treating hyperlipidaemia with a recognized capacity to prevent cardiovascular disease events. They inhibit β-hydroxy β-methylglutaryl-coenzyme A reductase, i.e. the rate-limiting enzyme in mevalonate pathway, reduce endogenous cholesterol synthesis, and increase low-density lipoprotein clearance by promoting low-density lipoprotein receptor expression mainly in the hepatocytes. Statins have pleiotropic effects including stabilization of atherosclerotic plaques, immunomodulation, anti-inflammatory properties, improvement of endothelial function, antioxidant, and anti-thrombotic action. Despite all beneficial effects, statins may elicit adverse reactions such as myopathy. Studies have shown that mitochondria play an important role in statin-induced myopathies. In this review, we aim to report the mechanisms of action of statins on mitochondrial function. Results have shown that statins have several effects on mitochondria including reduction of coenzyme Q10 level, inhibition of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation of Ca 2+ metabolism, and carnitine palmitoyltransferase-2 expression. The use of statins has been associated with the onset of additional pathological conditions like diabetes and dementia as a result of interference with mitochondrial pathways by various mechanisms, such as reduction in mitochondrial oxidative phosphorylation, increase in oxidative stress, decrease in uncoupling protein 3 concentration, and interference in amyloid-β metabolism. Overall, data reported in this review suggest that statins may have major effects on mitochondrial function, and some of their adverse effects might be mediated through mitochondrial pathways.

Polypharmacy and Malnutrition Management of Elderly Perioperative Patients with Cancer: A Systematic Review

“…Statins decrease the production of coenzyme Q 10 (CoQ 10 ) by inhibiting mitochondrial oxidative phosphorylation and inducing mitochondrial apoptosis [7,54]. Decreased CoQ 10 results in decreased adenosine triphosphate production and energy deficiency.…”

“…Mitochondrial function has been associated with myopathy, which is a side effect of taking statins. Since skeletal muscle is highly energy-consuming and deeply dependent on mitochondrial activity, mitochondrial dysfunction is largely associated with the development of statin-induced myopathy [54]. In a recent meta-analysis examining the effects of CoQ 10 on statin-induced myopathy, the concomitant use of CoQ 10 significantly improved statin-related muscle symptoms, such as muscle pain, muscle cramps, and muscle fatigue [55].…”

Pathogenetic mechanisms of statin dysglycemia and risk of new-onset diabetes

“…31 However, in in-vitro studies simvastatin directly inhibits L-type Ca 2+ channels in rat pancreatic islet β-cells, reducing activity in the channels, by attenuation of mitochondrial function. 33,35 Compared to normal control cells, simvastatin-treated cells had α lower insulin content, decreased insulin secretion, and less total insulin induced by low glucose level. 34 More recently, it has been suggested that statins may reduce membrane potential by inhibiting mitochondrial complex II activity, which causes oxidative stress.…”

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

“…For a long time, statins have been prescribed for patients with higher levels of cholesterol, LDL-C, and hypertriglyceridemia in patients with cardiovascular disorders and diabetes [17,18]. However, the current line of evidence has shown that statins have numerous lipid-independent (pleiotropic) actions [19][20][21][22][23][24][25][26]. Among the pleiotropic effects of statins is modulation of autophagy in various cells, providing a promising therapeutic strategy in treating disorders with impaired autophagy as primary underlying pathogenesis [27,28].…”