Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.
Overview
- Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, University College London, Gower Street,London, UK
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne,Cologne, Germany
- Max-Planck-Institute for Biology of Aging and Cologne Excellence Cluster for Ageing-associated Diseases,Cologne, Germany
- Department of Paediatric Neurology, Evelina London Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust,London, UK
- Department of Health and Biomedical Sciences, Universidad Loyola Andalucía,Seville, Spain
- Drug Discovery, UCL Wolfson Institute for Biomedical Research, University College London,London, UK
- Department of Genetics, University Medical Center Groningen, University of Groningen,Groningen, Netherlands
- Neuroscience Institute, National Research Council,Padua, Italy
- Department of Biomedical Sciences, University of Padua,Padua, Italy
- Department of Basic and Clinical Neuroscience, IoPPN, King’s College London,London, UK
- Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King’s College London,London, UK
Abstract
The autophagy-tethering factor ectopic P-granule 5 autophagy protein (EPG5) plays a key role in autophagosome-lysosome fusion. Impaired autophagy associated with pathogenic variants in EPG5 causes a rare devastating multisystem disorder known as Vici syndrome, which features neurodevelopmental defects, severe progressive neurodegeneration and immunodeficiency. The pathophysiological mechanisms driving disease presentation and progression are only partially understood. In patient-derived fibroblasts and iPS cells differentiated to cortical neurons, we find that impaired mitophagy leads to mitochondrial bioenergetic dysfunction. Physiological cytosolic Ca2+ transients result in unexpected mitochondrial Ca2+ overload despite a decrease in mitochondrial membrane potential. This is attributed to downregulation of MICU1. Ca2+ signals cause mitochondrial depolarisation, mtDNA release and activation of the cGAS-STING pathway, reversed by pharmacological inhibition of the mitochondrial permeability transition pore (mPTP) or of the STING pathway. Thus, we identify a pathophysiological cascade driving disease progression associated with EPG5 deficiency, including impaired mitochondrial bioenergetics, mitochondrial Ca2+ overload, vulnerability to mPTP opening and activation of innate immune signalling, signposting multiple potential therapeutic targets.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE316460, at NCBI GEO; found in “Data availability”
Data availability
The RNA-seq datasets generated and analysed during the current study are available in the GEO repository GSE316460 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 16 authors, 5 keywords, 20 MeSH terms, 2 funders, 92 references.
Cite
This paper
Singh, K., Dafsari, H. S., Gillham, O., Chi, H., Mandzhukova, I., Kourouzidou, I., Sheshadri, P., Chung, C.-Y., Pingitore, V., Vansenne, F., Selwood, D. L., Pendin, D., Szabadkai, G., Fanto, M., Jungbluth, H., & Duchen, M. R. (2026). Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation. Nature communications, 17(1), 6887. https://
BibTeX
@article{singh2026pathog
author = {Singh, Kritarth and Dafsari, Hormos Salimi and Gillham, Olivia and Chi, Haoyu and Mandzhukova, Ivet and Kourouzidou, Ioanna and Sheshadri, Preethi and Chung, Chih-Yao and Pingitore, Valeria and Vansenne, Fleur and Selwood, David L. and Pendin, Diana and Szabadkai, Gyorgy and Fanto, Manolis and Jungbluth, Heinz and Duchen, Michael R.},
title = {{Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation}},
journal = {Nature communications},
year = {2026},
month = may,
volume = {17},
number = {1},
pages = {6887},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/
url = {https://
pmid = {42191733},
pmcid = {PMC13388713}
}
RIS
TY - JOUR
AU - Singh, Kritarth
AU - Dafsari, Hormos Salimi
AU - Gillham, Olivia
AU - Chi, Haoyu
AU - Mandzhukova, Ivet
AU - Kourouzidou, Ioanna
AU - Sheshadri, Preethi
AU - Chung, Chih-Yao
AU - Pingitore, Valeria
AU - Vansenne, Fleur
AU - Selwood, David L.
AU - Pendin, Diana
AU - Szabadkai, Gyorgy
AU - Fanto, Manolis
AU - Jungbluth, Heinz
AU - Duchen, Michael R.
TI - Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/
VL - 17
IS - 1
SP - 6887
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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