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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

Authors

George Kelly

Tetsushi Kataura

Johan Panek

Gailing Ma

Hanna Salmonowicz

Ashley Davis

Hannah Kendall

Charlotte Brookes

Daniel Moscoh Ayine-Tora

Peter Banks

Glyn Nelson

Laura Dobby

Patricia R Pitrez

Laura Booth

Lydia Costello

Gavin D Richardson

Penny Lovat

Lino Ferreira

Laura Greaves

Karolina Szczepanowska

Thomas von Zglinicki

Satomi Miwa

Max Brown

Michael Flagler

John E Oblong

Charles C Bascom

Bernadette Carroll

Jóhannes Reynisson

Viktor I Korolchuk



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.]

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

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