Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities

Abstract

Peripheral artery disease (PAD) is a multifactorial disease initially triggered by reduced blood supply to the lower extremities due to atherosclerotic obstructions. It is considered a major public health problem worldwide, affecting over 200 million people. Management of PAD includes smoking cessation, exercise, statin therapy, antiplatelet therapy, antihypertensive therapy and surgical intervention. Although these pharmacological and non-pharmacological interventions usually increases blood flow to the ischemic limb, morbidity and mortality associated with PAD continue to increase. This scenario raises new fundamental questions regarding the contribution of intrinsic metabolic changes in the distal affected skeletal muscle to the progression of PAD. Recent evidence suggests that disruption of skeletal muscle mitochondrial quality control triggered by intermittent ischemia-reperfusion injury is associated with increased morbidity in individuals with PAD. The mitochondrial quality control machinery relies on surveillance systems that help maintaining mitochondrial homeostasis upon stress. In this review, we describe some of the most critical mechanisms responsible for the impaired skeletal muscle mitochondrial quality control in PAD. We also discuss recent findings on the central role of mitochondrial bioenergetics and quality control mechanisms including mitochondrial fusion-fission balance, turnover, oxidative stress and aldehyde metabolism in the pathophysiology of PAD, and highlight their potential as therapeutic targets.

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

“…Our results indicate that simvastatin prevented Ang II-induced severe mitochondrial swelling and vacuolization. In addition, simvastatin maintained mitochondrial length and dynamics through mitochondrial quality regulation (Ueta, Gomes, Ribeiro, Mochly-Rosen, & Ferreira, 2017).…”

Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities

“…Over the last decade, several studies have demonstrated that changes in mitochondrial function are critical to induce exercise benefits in heart failure [195]. Overall, exercise training improves the efficiency of mitochondrial oxidative phosphorylation [68], reduces mitochondrial permeability transition [68], increases the mitochondrial clearance of toxic molecules including ROS and aldehydes [196,197] and increases mitochondria number, size and clearance [68] in heart failure. In this context, exercise training would improve left ventricular function in heart failure animals by reestablishing mitochondrial functionality.…”

Mitochondrial Fission Inhibitors Suppress Endothelin-1-Induced Artery Constriction

“…Under physiological conditions, fusion and fission processes are balanced [6, 7]. However, under certain pathological conditions, the fission process is increased and the excessive mitochondrial fission promotes the disease progression; for instance, the mitochondrial fission increases in endothelial cells in diabetic states and in pulmonary artery smooth muscle cells in pulmonary arterial hypertension, and the increased mitochondrial fission contributes to the impairment of endothelial function in diabetes and hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension [8, 9].…”