Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

Abstract

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The agerelated accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. oxidative stress; mitophagy; fusion and fission; neurodegeneration; resveratrol THIS ARTICLE is part of a collection on Mitochondria in Cardiovascular Physiology and Disease. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.Advanced age is associated with excessive incidence and prevalence of cardiovascular disease (CVD). Over 80% of cases of coronary artery disease (CAD) and more than 75% of those of congestive heart failure (CHF) are observed in elderly patients (113). The incidence of CVD, including CAD, CHF, and stroke, increases from 4 -10/1,000 person-years in adults aged 45-54 years to 65-75/1,000 person-years in those older than 85 (112). CVD is also a major cause of chronic disability in advanced age (140). Indeed, subclinical CVD is associated with a decline in physical and cognitive function equivalent to over 5 years of aging (136). Similarly, neurodegenerative disorders, such as vascular dementia and Alzheimer's disease (AD), pose a major problem to global public health (45,90).Although the long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of CVD and neurodegeneration, intrinsic aging of the heart and the vasculature greatly enhances the susceptibility to developing CVD and neurodegenerative conditions in late life (100). The cardiovascular sy...

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis

“…10,16,27 In this study, we demonstrate that mitophagic elimination of damaged mitochondria has a pivotal role in regulation of mitochondrial ROS production, which is involved in acceleration of HBEC senescence in response to CSE exposure. PINK1 and PARK2 knockdown experiments clarify that both PINK1 and PARK2 are essential for mitophagy in response to CSE exposure and PINK1-mediated recruitment of PARK2 to mitochondria appears to be a prerequisite for ubiquitination and mitophagic recognition ( Fig.…”

“…Improper mitophagic elimination of damaged mitochondria has been implicated in the pathogenesis of a variety of diseases, 10,16,27 and we have recently demonstrated insufficient autophagy in COPD lung. 8,25 Hence, we assumed that our findings of accumulations of fragmented mitochondria might result from insufficient mitophagy in the airway epithelial cells of COPD lung and also in CSE-exposed HBEC.…”

“…2,[4][5][6][7][8][9] Although the molecular mechanism underlying cell senescence regulation is still unknown, reactive oxygen species (ROS) released during mitochondrial respiration has been generally implicated in the progression of cellular senescence. 3,10 Mitochondrial respiratory chain dysfunction accompanying enhanced ROS production can be attributed to cigarette smoke (CS) exposure, a main cause for COPD development. 11,12 Mitochondrial quality is maintained via the optimal balance between biogenesis and degradation for renewal, and mitochondria are also highly dynamic organelles undergoing continuous fusion and fission cycles.…”

Roles of SIRT3 in heart failure: from bench to bedside

“…Although some strategies, such as postconditioning, have been put forward to ameliorate the reperfusion injury, the incidences of total major cardiac events were not decreased (Hu et al, 2014). Several mechanisms have been discovered, including calcium overload, increased ROS formation, autophagy, apoptosis, and mitochondrial dysfunction (Murphy and Steenbergen, 2008;Marzetti et al, 2013). Intriguingly, these mechanisms interacted with each other.…”

Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-mediated hypertension.

“…Impaired mitochondrial dynamics such as excessive mitochondrial fission and decreased mitochondrial fusion is associated with cardiovascular diseases and diabetes [19][20][21][22]. Studies have implicated that HHcy facilitates excessive mitochondrial fission [23] and mitochondria-mediated cell death [24] however, the mechanisms are not well described.…”