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Lookup NU author(s): Jessie Nie, Professor Majlinda LakoORCiD, Professor Patrick Chinnery, Professor Rita HorvathORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026. Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.
Author(s): Hathazi D, Lyons C, Lagos D, Podmanicky O, Zarate-Mendez M, Nie Y, Muller JS, Allinson KSJ, Naylor H, Lako M, Elsharkawi I, Muffels I, Morava E, Kozicz T, Chinnery P, Lakatos A, Horvath R
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2026
Volume: 17
Online publication date: 21/06/2026
Acceptance date: 27/05/2026
Date deposited: 18/08/2026
ISSN (print): elec-tronic
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-026-74103-y
DOI: 10.1038/s41467-026-74103-y
Data Access Statement: The single-cell RNA sequencing data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE324301. Source data, including high-resolution scans of all blots presented in this paper, are provided as a Source Data file. All other data supporting the findings of this study are available within the paper and its Supplementary Information. This paper does not report any original code Source data are provided in this paper.
PubMed id: 42324264
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