Mitochondrial Respiration and Atherosclerosis: R-E-S-P-I-R-E. Find Out What it Means to Mϕ (and VSMC)

Atherosclerosis is an underlying cause of various cardiovascular diseases including coronary artery disease, chronic kidney disease, abdominal aortic aneurysm development, stroke, and heart failure.1,2 This progressive vascular disease is characterized by subendothelial lipoprotein retention, immune cell infiltration, a maladaptive inflammatory response, and vascular smooth muscle cell (VSMC)–mediated fibrous cap formation.1 As atherosclerotic lesions progress, cellular and tissue dysfunction give way to cell death and fibrous cap thinning, leading to thrombotic events and plaque rupture.3 See accompanying article on page 2322 Mitochondrial function is a critical regulator of cellular homeostasis because of its role in ATP production, ion transport, reactive oxygen species generation, and apoptotic signaling.4 Given the evidence for cellar dysfunction and the metabolic underpinning of atherosclerosis, mitochondrial dysfunction is largely hypothesized to contribute to lesion development and progression.5 Indeed, recent work has pointed to a role for mitochondrial reactive oxygen species (mitoROS) and mitochondrial DNA (mtDNA) damage in animal models of atherosclerosis.6,7 In particular, mtDNA damage has been found to precede lesion development, and genetic inhibition of mouse mitochondrial polymerase-γ exonuclease activity results in increased mtDNA damage, decreased respiratory function, and augmented lesion development and necrosis.8 In …