Investigating the causal relationships between mitochondrial proteins and dementia with Lewy bodies

Background Disruptions in mitochondrial function have been implicated in various neurodegenerative diseases. However, the specific role of mitochondrial proteins in the pathogenesis of dementia with Lewy bodies (DLB) remains poorly understood. Objective This study aims to investigate potential causal relationships between mitochondrial proteins and DLB risk using Mendelian randomization (MR) analysis. Methods Causal associations between 66 mitochondrial proteins (MPs) and DLB were assessed by MR analysis, utilizing data from comprehensive genome-wide association studies (GWAS), with various analytical methods, including the inverse variance weighted, MR-Egger, and weighted median. Cochran's Q statistics assessed the heterogeneity of instrumental variables. Results Genetic predispositions to increased levels of ES1 protein homolog and apoptosis-inducing factor 1 (AIF-1) were associated with an elevated risk of DLB. Conversely, genetic predispositions to increased levels of glutaredoxin-2 (GLRX-2), complement component 1 Q subcomponent-binding protein (C1QBP), and mitochondrial glutamate carrier 2 (GC2) were found to be protective against DLB. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy among the selected instrumental variables. Conclusions Our MR study identifies specific MPs potentially causally linked to DLB risk. These findings offer new insights into the MP-related mechanisms underlying DLB pathogenesis and highlight potential therapeutic targets.