Regional Mitochondrial Density Maps Selective Posterior Atrophy in Parkinson's Disease

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathobiology of Parkinson's disease (PD), yet the spatial relationship between regional energetic demand and patterns of neurodegeneration remains poorly understood, limiting mechanistic insight and development of disease-modifying therapies. OBJECTIVES: This study tested whether regional mitochondrial density aligns with patterns of brain atrophy in PD, how this alignment differs across genetic groups, and whether the mitochondrial-atrophy axis associates with motor and cognitive features. METHODS: Structural magnetic resonance imaging data were analyzed from 849 individuals (210 healthy controls, 639 patients with PD). Principal component analysis (PCA) identified dominant atrophy axes and tested their association with regional mitochondrial density and complex I activity. Transcriptomic validation used Allen Human Brain Atlas gene expression data restricted to 924 MitoCarta-annotated genes across 31 cortical regions. RESULTS: Participants with PD exhibited higher volumetric loss in limbic and subcortical regions than controls. PCA showed a posterior cortical axis of atrophy (PC3) that correlated positively with regional mitochondrial density and was more strongly expressed in LRRK2-PD than in sporadic PD. This axis was selectively associated with visuospatial dysfunction. Transcriptomic validation confirmed that regions of greater atrophy preferentially expressed mitochondrial genes, with mitoribosome assembly, mitochondrial DNA maintenance, and coenzyme Q biosynthesis emerging as the strongest pathway-level predictors. CONCLUSION: These findings link the brain's regional mitochondrial landscape to spatially patterned neurodegeneration in PD, with amplification in LRRK2 mutation carriers. This mitochondrial atrophy axis may provide a biologically informed marker aiding patient stratification and mitochondrial-targeted therapeutic development.