Mitochondrial dysfunction plays an important role in Parkinson’s disease (PD), with mitochondrial DNA copy number (mtDNA-CN) emerging as a potential marker for mitochondrial health. We investigated the links between blood mtDNA-CN and PD severity and risk using the Accelerating Medicines Partnership program for Parkinson’s Disease dataset, replicating our results in the UK Biobank. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. We estimated blood cell composition using complete blood cell profile when available or RNA-sequencing data as a surrogate. After adjusting for blood cell composition, the associations between mtDNA-CN and PD risk and clinical symptoms became non-significant. Bidirectional Mendelian randomization analysis also found no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Hence peripheral inflammatory immune responses rather than mitochondrial dysfunction underpin these previously identified associations in PD.

线粒体功能障碍在帕金森病 （PD） 中起着重要作用，线粒体 DNA 拷贝数 （mtDNA-CN） 成为线粒体健康的潜在标志物。我们使用帕金森病加速药物合作计划数据集研究了血液 mtDNA-CN 与 PD 严重程度和风险之间的联系，在英国生物样本库中复制了我们的结果。我们的研究结果表明，血液 mtDNA-CN 水平降低与 PD 风险增加以及运动症状和嗅觉功能障碍的严重程度增加有关。我们使用全血细胞谱（如果有）或 RNA 测序数据作为替代指标来估计血细胞组成。调整血细胞组成后，mtDNA-CN 与 PD 风险和临床症状之间的关联变得不显著。双向孟德尔随机化分析也发现没有证据表明血液 mtDNA-CN 与 PD 易感性之间存在直接因果关系。因此，外周炎性免疫反应而不是线粒体功能障碍是 PD 中这些先前发现的关联的基础。