Dataset Information

Mitophagy Activation by Urolithin A to Target Muscle Aging.

ABSTRACT: The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.

SUBMITTER: Faitg J

PROVIDER: S-EPMC10791945 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Mitophagy Activation by Urolithin A to Target Muscle Aging.

Faitg Julie J D'Amico Davide D Rinsch Chris C Singh Anurag A

Calcified tissue international 20231105 1

The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserv ...[more]

PMID: 37925671

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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 Activation by Urolithin A to Target Muscle Aging.

Publications

Mitophagy Activation by Urolithin A to Target Muscle Aging.

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