A study identifies two subtypes of idiopathic Parkinson's disease (iPD) based on the severity of neuronal respiratory complex I (CI) deficiency. The CI-deficient (CI-PD) subtype accounts for approximately a fourth of all iPD cases and is characterized by widespread neuronal CI deficiency, distinct gene expression profiles, increased mtDNA deletions, and a non-tremor dominant phenotype. In contrast, the non-CI-deficient (nCI-PD) subtype shows no mitochondrial impairment outside the dopaminergic substantia nigra and has a tremor dominant phenotype. These findings suggest that iPD has biological heterogeneity, with distinct molecular and clinical profiles in the two subtypes. CI-PD is associated with a non-TD phenotype, higher female prevalence, and lower ethanol consumption, while nCI-PD shows no significant differences in mtDNA deletion levels compared to controls. Transcriptomic analyses reveal distinct gene expression profiles between the subtypes, with CI-PD showing downregulation of OXPHOS-related genes and nCI-PD showing altered expression in multiple PD-linked pathways. Single-nuclei RNA-seq data further highlight cell-type-specific differences, with CI-PD showing mitophagy activation in microglia and nCI-PD showing oligodendrocyte involvement. These findings suggest that CI-PD and nCI-PD may have distinct pathogenic mechanisms and could benefit from different therapeutic approaches. The study highlights the importance of stratifying iPD based on molecular features rather than clinical profiles to improve understanding and treatment strategies.A study identifies two subtypes of idiopathic Parkinson's disease (iPD) based on the severity of neuronal respiratory complex I (CI) deficiency. The CI-deficient (CI-PD) subtype accounts for approximately a fourth of all iPD cases and is characterized by widespread neuronal CI deficiency, distinct gene expression profiles, increased mtDNA deletions, and a non-tremor dominant phenotype. In contrast, the non-CI-deficient (nCI-PD) subtype shows no mitochondrial impairment outside the dopaminergic substantia nigra and has a tremor dominant phenotype. These findings suggest that iPD has biological heterogeneity, with distinct molecular and clinical profiles in the two subtypes. CI-PD is associated with a non-TD phenotype, higher female prevalence, and lower ethanol consumption, while nCI-PD shows no significant differences in mtDNA deletion levels compared to controls. Transcriptomic analyses reveal distinct gene expression profiles between the subtypes, with CI-PD showing downregulation of OXPHOS-related genes and nCI-PD showing altered expression in multiple PD-linked pathways. Single-nuclei RNA-seq data further highlight cell-type-specific differences, with CI-PD showing mitophagy activation in microglia and nCI-PD showing oligodendrocyte involvement. These findings suggest that CI-PD and nCI-PD may have distinct pathogenic mechanisms and could benefit from different therapeutic approaches. The study highlights the importance of stratifying iPD based on molecular features rather than clinical profiles to improve understanding and treatment strategies.