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.

Keywords: 4-Hydroxynonenal; Mitochondrial dynamics; Mitochondrial metabolism; Mitophagy; Myocyte; Redox balance.

Figure 1

Schematic panel showing the process of ischemia-reperfusion injury triggered by exercise-rest cycles in PAD patients with intermittent claudication. During exercise, there is an increased skeletal muscle energy demand. However, limited limb energy transferring due to impaired blood flow and mitochondrial dysfunction causes a metabolic deficit and consequent exercise cessation. After cessation of exercise [and consequent reperfusion of the ischemic limb] mitochondria-mediated energy transferring is reestablished. However, intrinsic changes occurred during repeated cycles of ischemia-reperfusion injury cause mitochondrial dysfunction and accumulation of reactive oxygen species, therefore, contributing to a progressive metabolic deficit and skeletal muscle degereration in PAD.

Figure 2

Schematic panel showing the most critical systems involved in the mitochondrial quality control in PAD. Mitochondrial Detox System: Mitochondrial dysfunction, accumulation of reative oxygen species (ROS) and consequent generation of 4-hydroxynonenal (4-HNE) in the affected skeletal muscle contribute to the PAD pathophysiology. Therapies targeting mitochondria (Alda-1, MTP-131 and catalase overexpression) improves mitochondrial detox system and provide a better PAD outcome. Mitochondrial Dynamics: In general, large GTPases regulate mitochondrial fission (Drp1 and Fis1) and fusion (mfn1, mfn2 and Opa1). The peptide p110 inhibits mitochondrial fragmentation and ROS production.. Mitophagy: Damaged mitochondria can be sequestered by autophagosomes. The autophagosomes then fuse with lysosomes to degrade sequestered mitochondria.

Figure 3

Representative transmission electron microscopy (TEM) images of plantaris muscle four weeks after sham (control, upper panels) or hindlimb ischemia surgeries (lower panels) in mice. Circle and arrows in red indicate intermyofibrillar mitochondria. Circle and arrows in yellow indicate subsarcolemmal mitochondria. Asterisks indicate swollen mitochondria. Note that intermyofibrillar mitochondria from mice subjected to hindlimb ischemia are either elongated/clustered close to myofiber derangements (red circle) or smaller/sparse in intact areas. There is also accumulation of smaller mitochondria at subsarcolema four weeks after hindlimb ischemia surgery. These findings depict a disruption of mitochondrial morphology and connectivity after hindlimb ischemia.