Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease

• Published in: Nature communications 2024-04, Vol.15 (1), p.3631-3631, Article 3631
• Main Authors: Flønes, Irene H., Toker, Lilah, Sandnes, Dagny Ann, Castelli, Martina, Mostafavi, Sepideh, Lura, Njål, Shadad, Omnia, Fernandez-Vizarra, Erika, Painous, Cèlia, Pérez-Soriano, Alexandra, Compta, Yaroslau, Molina-Porcel, Laura, Alves, Guido, Tysnes, Ole-Bjørn, Dölle, Christian, Nido, Gonzalo S., Tzoulis, Charalampos
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 14/63; 38/77; 38/91; 631/208/212/2019; 631/378/1689/1718; 692/617/375/1718; Aged; Clinical medicine; DNA, Mitochondrial - genetics; Dopamine receptors; Electron transport chain; Electron Transport Complex I - deficiency; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Female; Gene expression; Heterogeneity; Hospitals; Humanities and Social Sciences; Humans; Hypotheses; Male; Middle Aged; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial DNA; Movement disorders; multidisciplinary; NADH-ubiquinone oxidoreductase; Neurodegenerative diseases; Neurons - metabolism; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Phenotype; Phenotypes; Science; Science (multidisciplinary); Substantia nigra; Substantia Nigra - metabolism; Substantia Nigra - pathology; Tremor; Tremors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47867-4

Idiopathic Parkinson’s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies. Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.