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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, Professor Gavin RichardsonORCiD, Professor Penny Lovat, Professor Laura GreavesORCiD, Professor Thomas von Zglinicki, Dr Satomi Miwa, Dr Bernadette Carroll, Professor Viktor KorolchukORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
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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