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

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.

Fragile X‐associated tremor/ataxia syndrome: Regional decrease of mitochondrial DNA copy number relates to clinical manifestations

“…However, on the basis of our results we might infer that mtDNA copy number shows a functional threshold effect and below it might causes cellular dysfunction. In this regard, Foote and co‐workers have recently described a role of mtDNA‐mediated mitochondrial dysfunction in cardiovascular disease . They identify that mtDNA copy number directly regulate the onset and progression of vascular aging in mice .…”

“…Possible explanation is that a fraction of non‐functional mtDNA is present within the total population or is a component of non‐functional mitochondria. Conversely, it has been recently demonstrated that augmenting mtDNA copy number enhances mitochondrial respiration, opening a path for a possible treatment target. Further studies using neuronal cells are necessary to confirm the direct effect of mtDNA copy number in mitochondrial function.…”

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…Altered mtDNA copy number (mtDNA-CN) and increased mutations render impaired mtDNA integrity, causing cellular dysfunction during aging [75]. A calculation of mtDNA-CN by the relative ratio of DNA from the mitochondrial gene NADH dehydrogenase subunit to the nuclear gene cytochrome P4501A1 found that mtDNA-CN decreased in angiotensin (Ang) II-induced cardiac hypertrophy mice [70].…”

Voluntary wheel running has no impact on brain and liver mitochondrial DNA copy number or mutation measures in the PolG mouse model of aging

“…These data also add to the current understanding of PolG mice in particular. Previous studies found that mtDNA copy number decreases with age (5,30). Our results showed slightly decreased mtDNA copy number with age, though it was not statistically significant.…”

“…As a result, PolG mice accumulate mitochondrial DNA (mtDNA) mutations leading to premature aging phenotypes including hair loss, weight loss, kyphosis, increased rates of apoptosis, organ damage, and eventually, an early death at around 12 months (2–4). PolG animals have also been reported to have a depletion of mtDNA copy number (4), or the number of mtDNA molecules per nuclear genome, which is generally associated with a decrease in mitochondria and energy production (4,5).…”