The Rise of Mitochondria in Peripheral Arterial Disease Physiopathology: Experimental and Clinical Data

Abstract

Peripheral arterial disease (PAD) is a frequent and serious condition, potentially life-threatening and leading to lower-limb amputation. Its pathophysiology is generally related to ischemia-reperfusion cycles, secondary to reduction or interruption of the arterial blood flow followed by reperfusion episodes that are necessary but also—per se—deleterious. Skeletal muscles alterations significantly participate in PAD injuries, and interestingly, muscle mitochondrial dysfunctions have been demonstrated to be key events and to have a prognosis value. Decreased oxidative capacity due to mitochondrial respiratory chain impairment is associated with increased release of reactive oxygen species and reduction of calcium retention capacity leading thus to enhanced apoptosis. Therefore, targeting mitochondria might be a promising therapeutic approach in PAD.

Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis

“…Indeed, the RNA-sequencing data from the referenced study was made publicly available and was analyzed for this report. Muscle mitochondrial dysfunction has been demonstrated to be a key event in PAD [ 32 ]. Decreased oxidative capacity due to mitochondrial respiratory chain impairment is associated with an increased release of reactive oxygen species, leading to a reduction of calcium retention, and apoptosis [ 32 ].…”

“…Muscle mitochondrial dysfunction has been demonstrated to be a key event in PAD [ 32 ]. Decreased oxidative capacity due to mitochondrial respiratory chain impairment is associated with an increased release of reactive oxygen species, leading to a reduction of calcium retention, and apoptosis [ 32 ]. However, detailing the intricacy of mitochondrial dysfunction is time-consuming and expensive, which may limit its utility in precision diagnosis and treatment [ 33 , 34 ].…”

Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases

“…Mitochondrial dysfunction might be inferred from tissues' or cells' oxygen consumption (reflecting mitochondrial oxidative capacity) and the mitochondrial membrane potential (reflecting the ability of the electron transport system to maintain the gradient of proton driving ATP production). Thus, the failure of mitochondria to produce ATP results in an energy deficit, impairing cells, and finally, organ function [14][15][16][17][18][19].…”

Mitochondria at the Crossroads of Physiology and Pathology

“…Notably, mitochondrial dysfunction of muscle cells represents a key event in the prognosis of peripheral arterial disease. Reduced OXPHOS activity due to ETC impairment increases ROS levels and Ca 2+ release from mitochondria, causing apoptosis [ 24 ]. However, if ROS levels remain below a threshold, the cells activate a defense program involving production of antioxidants and increased mitochondrial biogenesis.…”

“…However, if ROS levels remain below a threshold, the cells activate a defense program involving production of antioxidants and increased mitochondrial biogenesis. These mechanisms, known as mitohormesis, can limit the damage caused by repeated cycles of ischemia-reperfusion in peripheral arterial disease [ 24 ]. Pharmacological treatments that can improve mitohormesis might be a promising therapeutic approach for peripheral arterial disease and other cardiovascular diseases.…”