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. Our study aimed to assess the association between blood mtDNA-CN and PD, as well as to uncover the underlying mechanisms. Introducing mitoCN, a novel mtDNA-CN estimator adjusting for coverage bias, suitable for large-scale whole-genome sequencing data, we applied it across six cohorts within the Accelerating Medicines Partnership program for Parkinson's Disease dataset. We investigated the links between blood mtDNA-CN and both PD risk and severity, leveraging comprehensive clinical assessments. Our findings reveal that reduced blood mtDNA-CN levels are associated with heightened PD risk and increased severity of motor symptoms and olfactory dysfunction. However, upon adjusting for blood composition, these associations largely disappeared, indicating a predominant influence of changes in blood variables. Furthermore, using bidirectional Mendelian randomization, we explored causal relationships, finding no evidence of a direct causal relationship between blood mtDNA-CN and PD susceptibility. Thus, even though blood bulk mtDNA-CN correlates with an elevated risk of PD and more severe PD symptoms, our refined analyses and results suggest that peripheral immune dysfunction rather than mitochondrial dysfunction underpins these previously identified associations.

The authors have declared no competing interest.

This study was funded by the Michael J Fox Foundation for Parkinson's Research (MJFF) and the Shake It Up Australia Foundation (MJFF-021399). MB was supported by an NHMRC Investigator Grant (GNT1195236). This work was also supported by the Australian State of Victoria's Government's Operational Infrastructure Support Program, the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS), and the Felton Bequest.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Human Research Ethics Committee (HREC) of the Walter and Eliza Hall Institute of Medical Research gave ethical approval for this work (HREC reference 17/09LR and 22/19). All components of this study were conducted in accordance with the principles embodied within the Declaration of Helsinki.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Access to the AMP PD data is available through the Terra platform upon completion of an AMP PD access application (https://www.amp-pd.org/register-for-amp-pd). UK Biobank (UKB) phenotype and WGS data can be obtained through the UKB Research Analysis Platform following the submission of a UKB access application (https://ukbiobank.dnanexus.com/landing). Individual-level data, mtDNA-CN estimates, generated as part of AMP PD have been returned to enable utilization of the full individual-level data by the broader scientific community through the Terra workspace (https://app.terra.bio/#workspaces/bahlo_lab_amp_pd/MJFF-021399/data).