Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty
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.
Section snippets
Autophagy and mitophagy in cardiomyocytes
As an organ virtually postmitotic, the heart is among the most robust autophagy recipients of the body and relies on this degradative route for maintaining homeostasis (Sun et al., 2015). In keeping with this is the observation that upregulation of autophagy and mitophagy occurs following ischemia-reperfusion (I-R) and sepsis (Hoshino et al., 2012). Furthermore, an attenuation of stress-induced mitochondrial autophagy, accompanied by altered mitochondrial function and impaired cardiac function,
Mitochondrial-derived vesicles: mitophagy add-ins
An ever-growing amount of evidence indicates that, along with mitophagy, an additional process operating via endo-lysosomal trafficking contributes to MQC and mitochondrial homeostasis. This route, conserved from bacteria to eukaryotes, signals via vesicles budding. A large set of membranous shuttles is produced and vesicles of mitochondrial origin, named mitochondrial-derived vesicles (MDVs), deliver specific organellar components to late endosome/multivesicular bodies for recycling purposes (
Cell-free mtDNA: mitochondrial signaling beyond organelle's boundaries
Nucleic acids, including genomic DNA, mitochondrial DNA (mtDNA), viral DNA, and RNA (e.g., mRNA and microRNAs) may be retrieved in the circulation as cell-free molecules (Helmig et al., 2015). High circulating levels of nucleic acids have been identified in several conditions, including CVD (González-Masiá et al., 2013; Suzuki et al., 2008). The molecular mechanisms mediating their cellular release are unclear (Muotri et al., 2007). However, their unloading mostly occurs from injured
Is mitophagy a therapeutic target in cardiac aging? State of the art and future perspectives
The accrual of dysfunctional mitochondria is a well-established phenotypic alteration of the aged heart and evidence indicates that mitophagy impairment is a major contributor to organelle dyshomeostasis and tissue dysfunction (Eisenberg et al., 2016; Inuzuka et al., 2009; Ren et al., 2017; Wang et al., 2019). Genetic and pharmacological interventions targeting mitophagy have shown great potential towards extending lifespan in preclinical models (Table 1) (Ryu et al., 2016; Schiavi et al., 2015
Funding
This work was partly supported by an intramural grant from the Università Cattolica del Sacro Cuore (D1.2020) e by the nonprofit research foundation “Centro Studi Achille e Linda Lorenzon”.
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