Mitophagy as a guardian against cellular aging

Abstract

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.

Keywords: Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence.

Figure 1.

Basal mitophagy is a guardian against cellular senescence and aging. In young and proliferating human primary cells, basal mitophagy is highly active and acts as a safeguard against cellular senescence and aging phenotypes. The PINK1-PRKN-SQSTM1 pathway targets ROS-enriched mitochondria, via redox-sensitive cysteine residues of SQSTM1, leading to SQSTM1 oligomerization and subsequent mitophagy activation. In aged and senescent cells, alterations in the mitochondrial network, namely excessive mitochondrial fusion partially mediated by MFN2, hinders basal mitophagy, initiating cellular senescence programs. Small molecule interventions, such as STOCK1N-57534 that activates redox-regulated SQSTM1 oligomerization, can reactivate mitophagy in aged and senescent cells and improve cellular aging phenotypes.