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However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how\n                      <jats:italic>POLG<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>POLG<\/jats:italic>\n                      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\u2013V, 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD\u207a metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08706-w","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:26:44Z","timestamp":1785472004000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease"],"prefix":"10.1186","volume":"24","author":[{"given":"Anbin","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsering","family":"Yangzom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth John","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-4218","authenticated-orcid":false,"given":"Kristina Xiao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"issue":"2","key":"8706_CR1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1007\/s00018-010-0530-4","volume":"68","author":"JD Stumpf","year":"2011","unstructured":"Stumpf JD, Copeland WC. 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The study was approved by the Regional Committee for Medical and Health Research Ethics (REK, Norway; approval no. 2012\/919). Reprogramming and all subsequent experimental procedures were conducted under approved institutional and national guidelines. The human ESC line 360 (Karolinska Institute, Sweden) was used in compliance with institutional approval (approval no. 2012\/919).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors have read and approved the final manuscript and agree to its publication.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"988"}}