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.
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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
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