Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty

Highlights

• Cardiovascular disease is highly prevalent in older adults.

• Cardiomyocytes rely mostly on oxidative metabolism for their function.

• Oxidant-producing mitochondria have been identified in aged cardiomyocytes.

• Altered mitochondrial quality control and oxidative stress may contribute to cardiac frailty.

• Mitophagy and mitochondrial-derived vesicles may be targeted against cardiac aging.

Abstract

Cardiovascular disease is highly prevalent among older adults and poses a huge burden on morbidity, disability, and mortality. The age-related increased vulnerability of the cardiovascular system towards stressors is a pathophysiological trait of cardiovascular disease. This has been associated with a progressive deterioration of blood vessels and decline in heart function during aging. Cardiomyocytes rely mostly on oxidative metabolism for deploying their activities and mitochondrial metabolism is crucial to this purpose. Dysmorphic, inefficient, and oxidant-producing mitochondria have been identified in aged cardiomyocytes in association with cardiac structural and functional alterations. These aberrant organelles are thought to arise from inefficient mitochondrial quality control, which has therefore been place in the spotlight as a relevant mechanism of cardiac aging. As a result of alterations in mitochondrial quality control and redox dyshomeostasis, mitochondrial damage accumulates and contributes to cardiac frailty. Herein, we discuss the contribution of defective mitochondrial quality control pathways to cardiac frailty. Emerging findings pointing towards the exploitation of these pathways as therapeutic targets against cardiac aging and cardiovascular disease will also be illustrated.

Introduction

Cardiovascular disease (CVD) poses a huge morbidity, disability and mortality burden on the general population and is highly prevalent among older adults (Virani et al., 2020). People aged 80 years and older are at higher risk of heart failure, atrial fibrillation, and related stroke (Virani et al., 2020). Age-related increased vulnerability of the cardiovascular system towards stressors has been associated with progressive deterioration of blood vessels and decline in heart function (Chiao and Rabinovitch, 2015). In particular, an increase in heart mass, ventricular wall thickness, and cardiomyocyte cross-sectional area have been indicated as phenotypical manifestations of cardiac aging (Tracy et al., 2020).

Cardiomyocytes rely mostly on oxidative metabolism for deploying their activities and mitochondria are crucial organelles for cardiac functioning by supplying energy for myocardial contraction (Bertero and Maack, 2018; Murphy et al., 2016). Cardiac tissue is enriched in mitochondria that account for about 30% of myocellular volume with the ability of using several metabolic substrates to generate ATP under a wide range of physiological and pathological conditions (Bertero and Maack, 2018; Murphy et al., 2016). Along with their role of the cell's powerhouse, mitochondria are also a hub of several other activities including the regulation of metabolic reactions, cell death, calcium storage, and reactive oxygen species (ROS) production (Picca et al., 2021).

Dysmorphic and inefficient, high ROS-producing mitochondria have been described in aged cardiomyocytes (Dutta et al., 2012) together with cardiac structural and functional alterations (Marzetti et al., 2009). Therefore, mitochondrial dysfunction and inefficient mitochondrial quality control (MQC) processes have been placed in the spotlight as factors in cardiac aging (Picca et al., 2018a). Defective MQC and the installment of oxidative stress in the heart may be envisioned as an outcome of unsuccessful aging rather than a phenotypic expression of aging itself (Inglés et al., 2014). Indeed, altered quality control signaling and imbalanced oxidant defense may contribute to cardiac frailty as a result of damage accumulation not fully compensated by resilience mechanisms. When approaching the late stages of life, resiliency may become overwhelmed and stressors may cause rapid and unopposed damage accumulation that leads to frailty and eventually death. Accelerated aging may ensue because of either faster rates of damage accumulation or rapid shrinking and eventual collapse of resilience (Ferrucci et al., 2020). In this setting, peculiar cardiac ultrastructural changes have also been observed and associated with physical frailty (Pelà et al., 2021b, Pelà et al., 2021a).

Physical activity and exercise are recognized strategies and highly recommended interventions to prevent and manage CVD (Arnett et al., 2019; Haskell et al., 2007). Several observational studies have shown that the lack of compliance with physical activity recommendations is associated with an increased risk of myocardial infarction, coronary heart disease, stroke, and death (Blair et al., 1995; Chomistek et al., 2013; Held et al., 2012; Talbot et al., 2007). The effects of physical exercise on cardiovascular health go beyond prevention and also include significant changes in cardiac structure and function in the presence of CVD (Abad et al., 2017; C. Moraes-Silva et al., 2017; Feriani et al., 2018). Although many potential mechanisms have been suggested to explain such beneficial effects, improvements in mitochondrial function following physical exercise have received special attention (Guan et al., 2019).

Here, we discuss mitophagy and the generation of mitochondrial derived vesicles (MDVs) as relevant pathways in MQC and their involvement in cardiac frailty. The possibility of targeting MQC pathways to obtain therapeutic gain against cardiac aging is also discussed.