Antiaging Properties of a Grape-Derived Antioxidant Are Regulated by Mitochondrial Balance of Fusion and Fission Leading to Mitophagy Triggered by a Signaling Network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN
It was proposed that resveratrol, a polyphenolic antioxidant and a calorie restriction mimetic could promote longevity but subsequent studies could not prove this. The original proposal was based on the fact that a grape-derived antioxidant could activate the antiaging gene Sirt1. Most studies agree that indeed grape activates Sirt1, but a question remains whether Sirt1 is the cause or consequence of resveratrol treatment. Subsequently, mitochondrial Sirt3 was found to be activated. The present study on ischemic reperfusion (I/R) in rat hearts demonstrates that Foxo3a is activated subsequent to Sirt3 activation, which then activates PINK1. PINK1 potentiates activation of PARKIN leading to the activation of mitochondrial fission and mitophagy. Confocal microscopy conclusively shows the coexistence of Sirt3 with Foxo3a and Foxo3a with PINK1 and PARKIN. Mitophagy was demonstrated both by confocal microscopy and transmission electron microscopy. Western blot analyses data are consistent with the results of confocal microscopy. It appears that the grape-derived antioxidant modifies the intracellular environment by changing the oxidizing milieu into a reducing milieu and upregulating intracellular glutathione, potentiates a signal transduction cascade consisting of Sirt1/Sirt3-Foxo3a-PINK1-PARKIN-mitochondrial fusion fission-mitophagy that leads to cardioprotection, and paves the way to an anti-aging environment. 1. Introduction A growing body of evidence supports the crucial role of mitochondrial dynamics in aging process. Mitochondrial dysfunctions caused by morphological alterations and mitochondrial mtDNA mutations are intimately involved in aging [1]. Mitochondrion is continuously remodeled by two opposite processes, fusion and fission, contributing to mitochondrial dynamics. Fusion causes mixing of the intact mitochondria with slightly dysfunctional mitochondrial dynamics thereby replacing damaged mitochondrial DNA and restoring mitochondrial integrity [2]. Fission, on the other hand, sequesters irreversibly damaged mitochondria that are eliminated by the process involving autophagy of mitochondria (mitophagy) [3]. Mutations of PTEN-induced kinase 1 (PINK-1), a mitochondrial Ser/Thr kinase, regulate the oxidative phosphorylation machinery through mitochondrial fission [4]. PINK-1 activity is crucial for the development of heart through its role in maintaining mitochondrial function and redox homeostasis in cardiomyocytes [5]. PINK-1 in turn activates PARKIN, which translocates to depolarized mitochondria and promotes their degradation by mitophagy [6].
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