Did you know that there is a narrow relation between mitochondrial DNA and Parkinson’s disease?

    Mitochondria are the only organelles in the cells that contain their own genetic material (mtDNA). Specifically, human mtDNA is a double-stranded circular molecule of 16,569 base pairs that encodes 37 genes: 13 proteins essential for oxidative phosphorylation, 22 tRNAs, and 2 rRNAs. Each cell contains many mitochondria, and each mitochondrion carries multiple copies of mtDNA that varies between 5 to 10. Interestingly, mtDNA is inherited almost exclusively from the mother. Due to limited repair mechanisms and exposure to reactive oxygen species, mtDNA accumulates mutations faster than nuclear DNA. This could lead to cells containing a mixture of normal and mutated mtDNA. During human evolution, functional variants in mtDNA have been accumulated leading to the appearance of genealogical groups of mtDNA (named haplogroups) sharing a common maternal ancestor. These haplogroups are mostly separated among specific populations and geographic areas. Mutations in mtDNA are associated with mitochondrial disorders, neurodegenerative diseases, aging, and metabolic conditions. Pathological modifications in mitochondrial genome are classified in three wide groups: (1) mtDNA point mutations (inherited or somatic), (2) mtDNA deletions, and (3) alterations in the mtDNA copy number. Evidence suggests that genetic variations in mtDNA increases with age and may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer’s, Parkinson’s diseases (PD) or amyotrophic lateral sclerosis.

 Parkinson’s Disease and mtDNA

Several evidences have demonstrated that alterations in mitochondrial structures (such as mtDNA) and functions are involved in the onset and progression of neurodegenerative diseases, including Parkinson’s disease (PD). PD is the most common neurologic movement disorder affecting 2% of the population older than 60 years. Symptoms of PD include muscle rigidity, balance disturbances, and tremor. This neurodegenerative disease is characterized by progressive loss of dopaminergic neurons (DA) in substantia nigra par compacta (SNPC). DA are particularly exposed to higher levels of oxidative stress due to dopamine metabolism creating an environment favorable for alterations of mtDNA. Damage in mtDNA compromises mitochondrial bioenergetics and can lead to cell death. Which are the alterations in mtDNA associated to PD? Within the classification explained above, we can mainly find mtDNA deletions and alterations in the mtDNA copy number in a specific brain region or in a cell type-specific manner. For instance, mtDNA deletions and a reduced number in mtDNA copies are more prevalent in SNPC of patients with PD compared to patients with other movement disorders. Interestingly, in peripheral tissues (blood, muscle, fibroblasts) the results are more heterogeneous. Some studies report reduced mtDNA copy number in blood from PD patients but others find no change or even compensatory increases. Moreover, certain haplogroups have been shown to modulate susceptibility to develop PD. In European populations, haplogroups J and K are consistently associated with a reduced risk of PD, likely due to these variants promote slightly lower oxidative phosphorylation efficiency and reduced reactive oxygen species production and therefore limiting cumulative oxidative damage in DN. In contrast, some studies suggest that the haplogroup H, characterized by higher respiratory efficiency and increased oxidative stress, is associated with a modestly increased susceptibility to PD. Overall, mtDNA haplogroups act as genetic modifiers influencing in mitochondrial function and neuronal vulnerability.

 

To conclude, the scientific community has made significant advances in understanding the role of mtDNA copy numbers, haplogroups, mutations, and deletions in the physiopathology of PD and this might be considered the only neurodegenerative disease consistently associated with specific mtDNA haplogroups.

References: 

DOI: 10.1089/dna.2020.5398