#1

https://www.tandfonline.com/doi/full/10.1080/15548627.2024.2414461

Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N–57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N–57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(−like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.

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#2

you can request the full article here https://www.smartquantai.com

#3

Thanks for posting.
ChatGPT says ….

Mitophagy, the selective removal of damaged or dysfunctional mitochondria, can be enhanced by various physiological, lifestyle, and pharmacological interventions. These strategies improve mitochondrial quality and support cellular health. Below are the key factors that increase mitophagy:

Lifestyle and Physiological Factors
1. Exercise
• Regular physical activity (e.g., endurance and resistance training) stimulates mitophagy by increasing oxidative stress and energy demand.
• Pathways involved: AMPK activation, PGC-1α expression.
2. Fasting and Caloric Restriction
• Fasting or reducing caloric intake activates mitophagy by stimulating autophagy pathways.
• Key pathways: AMPK activation, inhibition of mTOR (mechanistic target of rapamycin).
3. Hormesis (Mild Stress Exposure)
• Cold exposure: Activates PGC-1α and promotes mitochondrial biogenesis and mitophagy.
• Heat exposure: Induces heat shock proteins that facilitate autophagy.

Nutritional and Dietary Factors
1. Ketogenic Diet
• Elevates ketone bodies (e.g., beta-hydroxybutyrate), which promote mitophagy.
2. Polyphenols
• Compounds like resveratrol, curcumin, and quercetin enhance mitophagy by activating SIRT1 and AMPK.
3. Pomegranate-Derived Urolithin A
• A metabolite of ellagitannins that specifically targets and enhances mitophagy.

Pharmacological Agents
1. Rapamycin
• Inhibits mTOR, a key suppressor of autophagy, promoting mitophagy.
2. NAD+ Precursors
• Compounds like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) enhance NAD+ levels, which support mitophagy through SIRT1 activation.
3. Metformin
• Activates AMPK and indirectly stimulates mitophagy.
4. Mitochondrial Uncouplers
• Mild mitochondrial stress (e.g., through agents like FCCP) can trigger mitophagy as a compensatory response.

Cellular and Molecular Triggers
1. Oxidative Stress
• Low to moderate levels of reactive oxygen species (ROS) serve as signals to activate mitophagy.
• Example: PINK1-Parkin pathway activation.
2. Hypoxia
• Low oxygen conditions activate HIF-1α, which promotes mitophagy.

By incorporating these interventions, mitophagy can be enhanced to maintain mitochondrial and cellular health, reduce inflammation, and support longevity.