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Mitophagy-promoting agents and their ability to promote healthy-aging.

ABSTRACT: The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.

SUBMITTER: Srivastava V

PROVIDER: S-EPMC10657188 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mitophagy-promoting agents and their ability to promote healthy-aging.

Srivastava Vijigisha V Gross Einav E

Biochemical Society transactions 20231001 5

The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process ...[more]

PMID: 37650304

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Project description:Compromised mitophagy and mitochondrial homeostasis are major contributors for the etiology of cardiac aging, although the precise underlying mechanisms remains elusive. Shank3, a heart-enriched protein, has recently been reported to regulate aging-related neurodegenerative diseases. This study aimed to examine the role of Shank3 in the pathogenesis of cardiac senescence and the possible mechanisms involved. Cardiac-specific conditional Shank3 knockout (Shank3CKO) mice were subjected to natural aging. Mitochondrial function and mitophagy activity were determined in vivo, in mouse hearts and in vitro, in cardiomyocytes. Here, we showed that cardiac Shank3 expression exhibited a gradual increase during the natural progression of the aging, accompanied by overtly decreased mitophagy activity and a decline in cardiac function. Ablation of Shank3 promoted mitophagy, reduced mitochondria-derived superoxide (H2O2 and O2•−) production and apoptosis, and protected against cardiac dysfunction in the aged heart. In an in vitro study, senescent cardiomyocytes treated with D-gal exhibited reduced mitophagy and significantly elevated Shank3 expression. Shank3 knock-down restored mitophagy, leading to increased mitochondrial membrane potential, decreased mitochondrial oxidative stress, and reduced apoptosis in senescent cardiomyocytes, whereas Shank3 overexpression mimicked D-gal-induced mitophagy inhibition and mitochondrial dysfunction in normally cultured cardiomyocytes. Mechanistically, the IP assay revealed that Shank3 directly binds to CaMKII, and this interaction was further increased in the aged heart. Enhanced Shank3/CaMKII binding impedes mitochondrial translocation of CaMKII, resulting in the inhibition of parkin-mediated mitophagy, which ultimately leads to mitochondrial dysfunction and cardiac damage in the aged heart. Our study identified Shank3 as a novel contributor to aging-related cardiac damage. Manipulating Shank3/CaMKII-induced mitophagy inhibition could thus be an optional strategy for therapeutic intervention in clinical aging-related cardiac dysfunctions. Graphical abstract Schematic diagram illustrating that elevated Shank3 in aged heart inhibited parkin-mediated mitophagy by directly binding with CaMKII, which ultimately leads to mitochondrial dysfunction and cardiac damage. Under cardiac aging, upregulated Shank3 binds with CaMKII to impede its mitochondrial translocation, suppressing mitochondrial translocation of Parkin and Parkin-mediated mitophagy. Mitophagy inhibition induced by Shank3/CaMKII binding evokes collapse of mitochondrial membrane potential, promotes mitochondria-derived superoxide production and mitochondria-dependent cardiomyocyte apoptosis, leading to aging-related cardiac dysfunction.Image 1 Highlights • Upregulated Shank3 and inhibited mitophagy activity are responsible for cardiac damage in the aged mice.• Shank3 inhibited mitophagy in the aged hearts by directly binding with CaMKII.• Shank3 ablation suppressed mitochondria-derived oxidative stress and apoptosis by promoting mitophagy.• Targeting mitophagy by regulating Shank3/CaMKII could be a new therapeutic target for aging-related cardiovascular diseases.

Dataset Information

Mitophagy-promoting agents and their ability to promote healthy-aging.

Publications

Mitophagy-promoting agents and their ability to promote healthy-aging.

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