Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice.

Kirsty Foote,Johannes Reinhold,Martin R Bennett,Michael P Murphy,Alison Finigan,Nichola L Figg,Emma P K Yu

doi:10.1111/acel.12773

Abstract

SummaryAging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β‐stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN‐regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase‐gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging.

Highlights

Aging of the large conduit arteries is a major cause of morbidity and mortality, contributing to hypertension and stroke
These data demonstrate that augmenting mtDNA copy number (mtCN) enhances mitochondrial respiration and delays both physiological and structural changes associated with vascular aging
To better understand how Twinkle expression delays vascular aging, we examined regulators associated with mtCN, mitochondrial mass and autophagy

Summary

| INTRODUCTION

Aging of the large conduit arteries is a major cause of morbidity and mortality, contributing to hypertension (high blood pressure) and stroke. Arterial aging is associated with multiple structural and functional changes, including vessel dilatation and wall thickening, loss of vascular smooth muscle cells (VSMCs) and elastin, deposition of collagen, endothelial dysfunction and low-grade inflammation. These changes (which are present in both humans (Wang et al, 2007) and rodents (Wang et al, 2006)) result in vessel stiffening. Dissecting the molecular mechanisms underlying vascular aging requires studies in animal models, and similar studies in rodents are more difficult to perform It is unclear what the earliest time points that constitute vascular aging in laboratory mice are, which physiological measures of large artery stiffness correspond most closely to humans, and whether similar processes underlie changes in mechanical properties in mouse and human arteries. Together these data highlight the direct role of mtDNA-mediated mitochondrial dysfunction in the progression of vascular aging

| RESULTS

Findings

| DISCUSSION

| EXPERIMENTAL PROCEDURES