ReviewMitophagy Receptors and Mediators: Therapeutic Targets in the Management of Cardiovascular Ageing
Introduction
Biological ageing is an irreversible evolutionary process typically accompanied with a gradual accumulation of damaged organelles and metabolites, which undermines organismal function including cardiovascular and metabolic homeostasis, ultimately leading to cardiac remodeling (thickening of the left ventricular wall), diastolic prolongation, endothelial dysfunction, and other cardiovascular defects (Nair and Ren, 2012; Obas and Vasan, 2018; Ren et al., 2018; Wu and Ren, 2019; Xu et al., 2016; Zhang et al., 2017). Biological ageing process (hereafter being referred to as “ageing”) provokes various cardiovascular diseases through genomic instability, reactive oxygen species (ROS) overproduction, telomere degradation, lipotoxicity, apoptosis, and mitophagy dysregulation (Calcinotto et al., 2019; Ceylan-Isik et al., 2013; Hua et al., 2011; Ren and Zhang, 2019; Wang et al., 2018b; Xu et al., 2016; Zhang et al., 2014). Among these culprit factors for cardiovascular ageing, mitophagy, a highly conservative process in all eukaryotes to remove and recycle long-lived or damaged mitochondria, has drawn some recent attention (Ren and Zhang, 2018b). Mitophagy along with mitochondrial fission and fusion (collectively termed as mitochondrial dynamics) maintains mitochondrial homeostasis and governs reconstruction of mitochondria (Hernandez-Resendiz et al., 2020). Moreover, mitophagy retards mitochondrial apoptosis via neutralization/engulfment of impaired mitochondria (Ajoolabady et al., 2020; Wu et al., 2019b). A plethora of experimental evidence has demonstrated a role for defective mitophagy in the dysregulation of mitochondrial homeostasis and therefore myocardial function (Gustafsson and Dorn, 2019). Mitophagy perturbation is known to disturb genome integrity, arrests biogenesis of mitochondria, and generates ROS, leading to mitochondrial cell death in the hearts (Hernandez-Resendiz et al., 2020). Ageing is one of the main culprit factors which compromises mitophagy homeostasis to elicit mitochondrial damage in cardiovascular system (Gustafsson and Dorn, 2019; Ren and Zhang, 2018b; Zhou et al., 2017b; Zhou et al., 2018c). Mitochondrial fragmentation and compromised mitophagy are both well documented in aged cardiovascular system (Gustafsson and Dorn, 2019; Zhou et al., 2018c). Several core elements of mitophagy including PTEN-induced kinase 1 (PINK1) are downregulated in ageing, consolidating a likely ageing-associated decline in mitophagy (Ren et al., 2017; Zhou et al., 2017c). Moreover, advanced ageing may underlie the accumulation of certain mitophagy proteins in the heart due to mitophagy dysregulation (Thai et al., 2019). Hence, therapeutic maneuver targeting mitophagy should help to alleviate and repair ageing-induced mitophagy defects in the cardiovascular system (Ren et al., 2018), which would preserve mitochondrial homeostasis and cardiovascular health in the elderly. In this context, this review aims to delineate the most recent advances in the field of molecular mitophagy and to summarize possible strategies for therapeutics targeting mitophagy in an effort to preserve cardiac health in the relam of global ageing.
Section snippets
Mitochondrial integrity in cardiovascular ageing
Mitochondria are dynamic intracellular organelles encapsulated by two membrane structures namely mitochondrial outer membrane (MOM) and mitochondrial inner membrane (MIM). To share metabolites, proteins, and membranes, mitochondria interconnect with each other or with other organelles such as lysosomes and endoplasmic reticulum (ER) (Liu et al., 2020; Ren et al., 2010). Mitochondria undergo constant fusion and fission. Mitofusin1 (Mfn1) and Mfn2 carry out MOM fusion, while optic atrophy 1
PINK1/Parkin-mediated mitophagy in mammalian cells
Under physiological mitochondrial homeostasis, the mitophagy signal PINK1 is translocated to MIM, where it is cleaved by mitochondrial proteasomes. However, with mitochondrial damage or depolarization, PINK1 translocation is hampered, leading to its accumulation at MOM. PINK1 then recruits E3 ubiquitin ligase, Parkin, and prompts its phosphorylation/activation, ultimately ubiquitination of target mitochondrial proteins. Moreover, PINK1 phosphorylates ubiquitin chains, to further recruit Parkin,
Overview of mitophagy in neurodegenerative diseases
Mitochondrial impairment manifested by ROS accumulation, ATP reduction, mtDNA damage, caspase-mediated apoptosis, and mitophagy dysregulation is a cardinal contributor to Parkinson’s disease (PD). Mutations of several core mitophagy elements including sterol regulatory element-binding protein 1 (SREBF1), WD40 domain protein 7 (FBXW7), PINK1, Parkin, Parkinson disease protein 7 (DJ-1), leucine-rich repeat kinase 2 (LRRK2), and α-synuclein (α-Syn) impair mitophagy and mitochondrial function in
Mitophagy dysregulation in cardiovascular ageing
Ample evidence has denoted interconnections between impaired mitophagy and cardiovascular ageing. Deficiency in mitophagy promotes ageing process, while ageing dampens physiological activation and homeostasis of mitophagy (Yang et al., 2019a). Thai and coworkers reported accumulation of Parkin in aged cardiomyocytes and HF due to defective mitophagy (Thai et al., 2019), suggesting that ageing may be characterized by mitochondrial damages which initially evoke compensatory mitophagy.
Involvement of mitophagy in lifespan and longevity
Modulation of mitochondria offers a novel approach for lifespan extension and longevity in mammals. For example, induction of mild mitochondrial uncoupling (mMUC) in a tissue-specific manner has been suggested to promote longevity (Klaus and Ost, 2020). Low consumption of 2,4-dinitrophenol (DNP) (an uncoupler for mitochondrial repiration) accompanied by a healthy diet resisted obesity, protected against T2D, and prolonged longevity by approximately 7% (Caldeira da Silva et al., 2008; Geisler,
Gender dependent mitophagy in cardiovascular ageing and disease
Mitochondrial quality control and mitophagy display sex differences, culminating in distinct health outcomes. For example, mitochondrial fission enhances in brain hemispheres from females in cerebral hypoxia-ischemia, while fission overtly rises in male brain ipsilateral hemisphere. Male brain seems to exhibit more basal autophagy and mitophagy activity compared with that from females (Demarest et al., 2016). Given the apparent gender differences in metabolism and cellular primary biofuels
Targeting mitophagy for management of cardiovascular ageing; opportunities and challenges
Mitophagy maintains mitochondrial quality and removes long-lived or defective mitochondria, which prevents ageing and alleviates ageing-associated pathological phenotypes (Wu et al., 2019b). As described in previous sections, ageing dysregulates molecules involved in mitophagy, although not necessarily all mitophagy regulators. In other words, given that mitophagy is dominated by a wide network of molecules and pathways, many of them might remain intact and uninfluenced during ageing. In this
Concluding remarks
Taken together mitophagy is a cytoprotective mechanism, dysfunction of which occurs in ageing leading to cardiovascular diseases. Exploiting strategies to induce mitophagy might mitigate ageing-induced cardiovascular damages leading to improved healthspan of elderly cardiovascular patients. Despite potential molecular targets for mitophagy induction, restricting protein uptake and implementing an active lifestyle might be the easiest strategies to repel ageing-induced damage to mitochondria and
Acknowledgments
The authors would like to thank Shanghai Institute of Cardiovascular Diseases, and Zhongshan Hospital, Fudan University, Shanghai, China, and Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran for their generous support. Work in our labs has been supported by the National Key R&D Program of China (2017YFA0506000), Natural Science Foundation of China (91749128, 81770261), Science and Technology Innovation Project
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