Objective: To determine whether specific mitochondrial DNA (mtDNA) haplogroup(s) affect the level of p-S65-Ub as quantitative marker of mitochondrial damage in Lewy Body Disease.

Background: Perturbations in lipid homeostasis, mitochondrial dysfunction, and lysosomal impairment have been indicated as the most prominent biological pathways contributing to LBD. During stress, PINK-PRKN label damaged mitochondria with phosphorylated Ub (pS65-Ub). Emerging evidence suggests that mitochondrial DNA variations also exhibit unique oxidative phosphorylation capacity, generation of reactive oxygen species, and thus overall disease susceptibility. However, the contribution of mtDNA variation to mitochondrial damage in LBD remains unknown.

Method: A total of 514 LBD cases from the brain bank for neurodegenerative disorders at the Mayo Clinic in Jacksonville, Florida were included in this study. Information was collected regarding age at death, sex, LBD subtype, Braak stage, Thal phase, pS65-Ub level in the hippocampus. All subjects were Caucasian, non-Hispanic, and unrelated. We also generated whole-genome sequencing data for the same 514 samples from the cerebellum. The mitochondrial DNA variations were extracted directly from the sequencing data results using Mitochondrial High-Performance Caller (MitoHPC). The association of each separate mitochondrial haplogroup with pS65-Ub level was evaluated using a linear regression model that was adjusted for age at death and sex, and where pS65-Ub level was assessed on the natural logarithm scale owing to its skewed distribution. Haplogroups that occurred in fewer than five subjects were summarized descriptively but were not included in association analysis.

Results: There was a significant association between presence of haplogroup V and a lower pS65-Ub level (β: -0.66, P=0.022). Additionally, though not quite significant, there was a trend toward an association between presence of haplogroup W and an increased pS65-Ub level (β: 0.65, P=0.085). No other notable associations between haplogroups and pS65-Ub were observed (all P≥0.24).

Conclusion: Our study highlights a strong association between mitochondrial DNA haplogroup V and p-S65-Ub. We are currently conducting a replication cohort study to validate these findings. To our knowledge, this is the first study to characterize the link between mtDNA haplogroup and pS65-Ub as a quantitative marker of mitochondrial quality control in LBD.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-mitochondrial-dna-haplogroup-and-ps65-ub-levels-in-lewy-body-disease/