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Mitophagy as a guardian against cellular aging

Lookup NU author(s): Dr Tetsushi Kataura, Niall Wilson, Gailing Ma, Professor Viktor KorolchukORCiD

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Abstract

© 2024 Informa UK Limited, trading as Taylor & Francis Group. 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.

Publication metadata

Author(s): Kataura T, Wilson N, Ma G, Korolchuk VI

Publication type: Note

Publication status: Published

Journal: Autophagy

Year: 2025

Volume: 21

Issue: 1

Pages: 249-251

Online publication date: 14/10/2024

Acceptance date: 06/10/2024

ISSN (print): 1554-8627

ISSN (electronic): 1554-8635

Publisher: Taylor and Francis Ltd.

URL: https://doi.org/10.1080/15548627.2024.2414461

DOI: 10.1080/15548627.2024.2414461

PubMed id: 39402011

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