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

Kelly G, Kataura T, Panek J, Ma G, Salmonowicz H, Davis A, Kendall H, Brookes C, Ayine-Tora DM, Banks P, Nelson G, …, Korolchuk VI · 2024 · Developmental Cell · Atlas ID KEL2024

What this study shows

Healthy primary human cells run a high level of basal mitophagy, started by mitochondrial superoxide and carried out through the PINK1/Parkin pathway with p62 as the selective receptor. That housekeeping shuts down on entry into senescence and in naturally aged cells. Blocking mitophagy in young proliferating cells was by itself enough to trigger the senescence program, and reactivation of mitophagy was necessary for the anti-senescence effect of rapamycin and of NAD precursors, which places part of rapamycin's action on cellular ageing downstream of mitochondrial quality control rather than beside it. A p62-targeting small molecule restored mitophagy and rescued markers of cellular ageing.

Abstract

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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).

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At a glance

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Evidence type M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Primary human cells; senescent and naturally aged cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type5 - Mechanistic / In Vitro
Model systemPrimary human cells; senescent and naturally aged cells
JournalDevelopmental Cell
Year2024
Peer reviewedYes
Record last updated2026-10-01
SourceDOI 10.1016/j.devcel.2024.04.020 · PMID 38897197

Where this study fits

How this study connects to the pathway map, open questions, people and other studies in the Atlas.

Open question

Mechanism-to-outcome gap · H10

How much of rapamycin's healthspan benefit runs through fewer senescent cells?

Cited there as evidence. Evidence stands at: Mechanism in cells.

People in the Atlas

  • George Kelly first author · 1 study in the Atlas

    Cell biologist from Viktor Korolchuk's group at Newcastle University who showed that the routine clearing of damaged mitochondria fails as human cells become senescent

  • Viktor I. Korolchuk last author · 5 studies in the Atlas

    Showed that where lysosomes sit inside the cell tunes mTORC1 activity to nutrient supply. His Newcastle lab found that senescent cells can no longer switch mTORC1 off when nutrients or growth factors are withdrawn, and studies how autophagy and mitophagy decline with age

  • Glyn Nelson 2 studies in the Atlas

    Microscopy specialist who manages Newcastle University's Bioimaging Unit and has worked for many years on the signalling networks that keep senescent cells in their arrested state

  • Penny Lovat 2 studies in the Atlas

    Professor of Cellular Dermatology and Oncology at Newcastle University who studies autophagy in melanoma, and whose work on the autophagy protein AMBRA1 and the skin protein loricrin underlies a test, developed with AMLo Biosciences, to identify early melanomas at low risk of spreading

  • Thomas von Zglinicki 2 studies in the Atlas

    Cell-senescence researcher who co-authored the Newcastle studies on stuck-on mTORC1 in senescent cells and on loss of basal mitophagy as a driver of cellular ageing.

More: 25 other authors
  • Satomi Miwa 2 studies in the Atlas

    Mitochondrial biologist who contributed to Newcastle studies on rapamycin in NF-κB-driven ageing mice and on basal mitophagy as a brake on cellular senescence.

  • Bernadette Carroll 3 studies in the Atlas

    First author of the study showing why mTORC1 stays switched on in senescent cells, and co-author on G3BP–TSC and senescence-mitophagy work; her own lab studies how nutrient sensing breaks down in ageing cells.

No profile yet: Kataura T, Panek J, Ma G, Salmonowicz H, Davis A, Kendall H, Brookes C, Ayine-Tora DM, Banks P, Dobby L, Pitrez PR, Booth L, Costello L, Richardson GD, Przyborski S, Ferreira L, Greaves L, Szczepanowska K, Brown M, Flagler M, Oblong JE, Bascom CC, Reynisson J

Related studies

More related studies

All 115 studies on Rapamycin

Topics

MitophagyRapamycinp62/SQSTM1Cellular senescence

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

InterventionMitophagy inhibition; rapamycin; NAD precursors; p62-targeting small molecule
TargetPINK1/Parkin/p62 basal mitophagy
ModelPrimary human cells (senescent and naturally aged)
EffectBasal mitophagy shuts down in senescence; blocking it induces senescence and reactivating it is needed for rapamycin's anti-senescence effect.

Cite this paper

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Kelly, G., Kataura, T., Panek, J., Ma, G., Salmonowicz, H., Davis, A., Kendall, H., Brookes, C., Ayine-Tora, D. M., Banks, P., Nelson, G., Dobby, L., Pitrez, P. R., Booth, L., Costello, L., Richardson, G. D., Lovat, P., Przyborski, S., Ferreira, L., Greaves, L., Szczepanowska, K., von Zglinicki, T., Miwa, S., Brown, M., Flagler, M., Oblong, J. E., Bascom, C. C., Carroll, B., Reynisson, J., & Korolchuk, V. I. (2024). Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule. Developmental Cell. https://doi.org/10.1016/j.devcel.2024.04.020

@article{KEL2024,
  author       = {Kelly, G. and Kataura, T. and Panek, J. and Ma, G. and Salmonowicz, H. and Davis, A. and Kendall, H. and Brookes, C. and Ayine-Tora, D. M. and Banks, P. and Nelson, G. and Dobby, L. and Pitrez, P. R. and Booth, L. and Costello, L. and Richardson, G. D. and Lovat, P. and Przyborski, S. and Ferreira, L. and Greaves, L. and Szczepanowska, K. and von Zglinicki, T. and Miwa, S. and Brown, M. and Flagler, M. and Oblong, J. E. and Bascom, C. C. and Carroll, B. and Reynisson, J. and Korolchuk, V. I.},
  title        = {{Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule}},
  journal      = {Developmental Cell},
  year         = {2024},
  doi          = {10.1016/j.devcel.2024.04.020},
  note         = {PMID: 38897197},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record KEL2024) [Data set]. https://mtor-atlas.org/study/KEL2024/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_KEL2024,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record KEL2024},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/KEL2024/},
  doi          = {10.5281/zenodo.22059963}
}
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