Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.

Kelly, George; Kataura, Tetsushi; Panek, Johan; Ma, Gailing; Salmonowicz, Hanna; Davis, Ashley; Kendall, Hannah; Brookes, Charlotte; Ayine-Tora, Daniel Moscoh; Banks, Peter; Nelson, Glyn; Dobby, Laura; Pitrez, Patricia R; Booth, Laura; Costello, Lydia; Richardson, Gavin D; Lovat, Penny; Przyborski, Stefan; Ferreira, Lino; Greaves, Laura; Szczepanowska, Karolina; von Zglinicki, Thomas; Miwa, Satomi; Brown, Max; Flagler, Michael; Oblong, John E; Bascom, Charles C; Carroll, Bernadette; Reynisson, Jóhannes; Korolchuk, Viktor I

Abstract

Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.]

Citation

Kelly, G., Kataura, T., Panek, J., Ma, G., Salmonowicz, H., Davis, A., …Korolchuk, V. I. (2024). Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule. Developmental Cell, Article S1534-5807(24)00295-8. https://doi.org/10.1016/j.devcel.2024.04.020

• Journal Article Type: Article
• Acceptance Date: Apr 28, 2024
• Online Publication Date: Jun 18, 2024
• Publication Date: Jun 18, 2024
• Deposit Date: Jul 10, 2024
• Publicly Available Date: Jul 10, 2024
• Journal: Developmental Cell
• Print ISSN: 1534-5807
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Article Number: S1534-5807(24)00295-8
• DOI: https://doi.org/10.1016/j.devcel.2024.04.020
• Keywords: aging, nicotinamide, rapamycin, senescence, redox, nicotinamide riboside, PINK1, p62, mitophagy, Parkin, autophagy
• Public URL: https://durham-repository.worktribe.com/output/2520427