Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.

Overview

1. Department of Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092 China
2. Department of Biomedicine (IBM), Faculty of Medicine, University of Bergen, Bergen, 5020 Norway
3. Department of Pediatric Research, Oslo University Hospital, Oslo, 0372 Norway
4. School of Medicine, Medical & Biological Sciences, University of St Andrews, North Haugh, St Andrews, KY16 9TF UK

Abstract

Background: POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined.

Methods: Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how POLG mutations alter mitochondrial and neuronal programs at subtype resolution. We analyzed dopaminergic neuronal populations and ventral midbrain neurons to define disease-associated transcriptional changes. To evaluate therapeutic improvement, POLG organoids were treated chronically with nicotinamide riboside (NR), followed by single-cell transcriptomic profiling and pathway enrichment analysis.

Results: POLG mutations induced a coordinated downregulation of genes associated with oxidative phosphorylation and synaptic signaling, particularly in terminally differentiated dopaminergic neurons. This transcriptional alteration involved genes encoding respiratory chain complexes I–V, mitochondrial translation machinery, and ATP synthase components, suggesting disruption of mitochondrial bioenergetic programs at the transcriptomic level. Among dopaminergic subtypes, DA2 neurons and ventral midbrain neurons showed the most pronounced transcriptional alterations, indicating maturation-dependent vulnerability. NR treatment was associated with altered expression of genes involved in oxidative phosphorylation, NADH dehydrogenase activity, respiratory chain assembly, and synaptic pathways. Following NR exposure, dopaminergic subpopulations exhibited changes in cell-type proportions and partial normalization of mitochondrial- and synaptic-related transcriptional programs.

Conclusions: These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD⁺ metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-026-08706-w.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE241743, at NCBI GEO; found in “Data availability”

Data availability

The RNA sequencing read count data has been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE241743 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE241743). All other datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 5 keywords, 13 MeSH terms, 52 references.

Cite

This paper

Chen, A., Yangzom, T., Sullivan, G. J., & Liang, K. X. (2026). Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease. Journal of translational medicine, 24(1), 988. https://doi.org/10.1186/s12967-026-08706-w

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