This study investigates the molecular heterogeneity of idiopathic Parkinson's disease (iPD) by stratifying it based on the severity of neuronal respiratory complex I (CI) deficiency. The research identifies two emerging disease subtypes: CI-iPD, characterized by widespread neuronal CI deficiency, distinct gene expression profiles, increased mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes, and nCI-iPD, which exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and a predilection for a tremor dominant phenotype. These findings provide insights into the biological heterogeneity of iPD, with implications for both mechanistic understanding and treatment strategies. The study uses immunohistochemistry, transcriptomics, and single-nuclei RNA sequencing to analyze brain tissue from two independent cohorts, confirming the existence of these subtypes in different populations. The results suggest that CI-iPD may be more responsive to treatments targeting mitochondrial dysfunction, while nCI-iPD may benefit from approaches targeting other pathways.This study investigates the molecular heterogeneity of idiopathic Parkinson's disease (iPD) by stratifying it based on the severity of neuronal respiratory complex I (CI) deficiency. The research identifies two emerging disease subtypes: CI-iPD, characterized by widespread neuronal CI deficiency, distinct gene expression profiles, increased mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes, and nCI-iPD, which exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and a predilection for a tremor dominant phenotype. These findings provide insights into the biological heterogeneity of iPD, with implications for both mechanistic understanding and treatment strategies. The study uses immunohistochemistry, transcriptomics, and single-nuclei RNA sequencing to analyze brain tissue from two independent cohorts, confirming the existence of these subtypes in different populations. The results suggest that CI-iPD may be more responsive to treatments targeting mitochondrial dysfunction, while nCI-iPD may benefit from approaches targeting other pathways.