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

Lookup NU author(s): George Kelly, Dr Tetsushi Kataura, Dr Johan PanekORCiD, Hanna Salmonowicz, Hannah Kendall, Charlotte Brookes, Dr Glyn NelsonORCiD, Laura Dobby, Laura Booth, Lydia Costello, Dr Gavin RichardsonORCiD, Professor Penny Lovat, Dr Laura Greaves, Professor Thomas von Zglinicki, Dr Satomi Miwa, Dr Bernadette Carroll, Dr Viktor Korolchuk

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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.

Publication metadata

Author(s): Kelly G, Kataura T, Panek J, Gailing M, Salmonowicz H, Davis A, Kendall H, Brookes C, Ayine-Tora DM, Banks P, Nelson G, Dobby L, Pitrez PR, Booth L, Costello L, Richardson GD, Lovat P, Przyborski S, Ferreira L, Greaves L, Szczepanowska K, von Zglinicki T, Miwa S, Brown M, Flagler M, Oblong JE, Bascom CC, Carroll B, Reynisson J, Korolchuk VI

Publication type: Article

Publication status: Published

Journal: Developmental Cell

Year: 2024

Pages: Epub ahead of print

Online publication date: 18/06/2024

Acceptance date: 28/04/2024

Date deposited: 26/06/2024

ISSN (print): 1534-5807

ISSN (electronic): 1878-1551

Publisher: Cell Press

URL: https://doi.org/10.1016/j.devcel.2024.04.020

DOI: 10.1016/j.devcel.2024.04.020

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