Mitophagy as a guardian against cellular aging.

Kataura, Tetsushi; Wilson, Niall; Ma, Gailing; Korolchuk, Viktor I.

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. Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.

CELLULAR aging; HOMEOSTASIS; REACTIVE oxygen species; IONIZING radiation; AGING prevention

Autophagy, 2025, Vol 21, Issue 1, p249

1554-8627

Academic Journal

10.1080/15548627.2024.2414461