A Less Effective Compensatory Response to Mitochondrial DNA Deletions Observed in Parkinson's Disease Patients
Mitochondria, the power plants of the cell, evolved from symbiotic bacteria, and still carry a remnant genome of their own, entirely separate from the nuclear DNA found in the cell nucleus. Unfortunately, mitochondrial DNA is prone to deletion mutations, either due to replication errors or oxidative reactions, and some types of deletion can form the basis for runaway cellular dysfunction. This process is one of the causes of degenerative aging, and doing something about it is one of the line items on the SENS rejuvenation research agenda. As it happens, mitochondrial DNA damage accumulates more readily in some tissues than in others. It is known that this is the case in the substantia nigra, for example, and that this susceptibility is connected to the development of Parkinson's disease, a condition caused by the loss of dopamine-generating neurons in that area of the brain. Researchers here provide evidence to support the contention that Parkinson's patients are distinguished from their comparatively healthy peers not by more mitochondrial damage, but rather by the lack of a compensatory generation of more undamaged mitochondrial DNA in the affected neurons:
Somatic mitochondrial DNA (mtDNA) damage has been associated with both normal aging and neurodegeneration. Accelerated mtDNA mutagenesis causes a premature aging phenotype in mice and somatic mtDNA deletions have been shown to accumulate with advancing age in post-mitotic tissues including the brain, heart and skeletal muscle. In the brain, the dopaminergic substantia nigra is particularly susceptible to somatic mtDNA deletions, which accumulate there at substantially higher levels compared with other areas of the brain. This predilection has led to the hypothesis that mtDNA damage plays a role in the pathogenesis of Parkinson disease (PD), where neurodegeneration of the substantia nigra is the main pathological hallmark and widely accepted as the cause of the cardinal clinical features.
mtDNA deletions were shown to accumulate at similar levels in both individuals with PD and healthy controls however, and therefore do not provide a sufficient explanation for the specific vulnerability of the substantia nigra in PD. Mice accumulating high levels of mtDNA deletion due to an error-prone mtDNA-polymerase (POLG) show a concomitant increase in mtDNA copy number which is associated with nigrostriatal survival and even resistance to mitochondrial respiratory chain complex-I inhibition. Although a similar protective mechanism has not yet been identified in humans, the importance of mtDNA copy-number regulation is highlighted by the vulnerability of the substantia nigra in inherited mtDNA-depletion disorders and the increased risk of PD associated with genetic variation in genes encoding key factors of mtDNA maintenance, such as the mtDNA polymerase γ (POLG) and mitochondrial transcription factor A (TFAM). Nevertheless, the precise mechanism by which mtDNA copy-number loss contributes to brain aging and neurodegeneration remains unclear.
We hypothesized that dopaminergic substantia nigra neurons in PD are rendered vulnerable to the effects of age-dependent mitochondrial mutagenesis due to an underlying dysregulation of mtDNA homeostasis. To test our hypothesis, we employed an integrative approach to study the complete spectrum of mtDNA changes in individual neurons from individuals with PD and controls. Our sample was derived from a population-based, prospectively collected and extensively characterized cohort. To ensure our sample was homogenous and representative for sporadic PD, we excluded known monogenic causes of PD by whole-exome sequencing. Neuropathological examination confirmed Lewy-body disease in all PD samples, whereas control samples were negative for neurodegenerative markers. Our results show that dopaminergic substantia nigra neurons of individuals with PD accumulate higher levels of somatic mtDNA deletions, but not point mutations, compared with age-matched controls. Moreover, in healthy individuals, mtDNA copy number increases with age, thus maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. Conversely, mtDNA copy number does not increase in individuals with PD, resulting in depletion of the wild-type mtDNA population. Our findings suggest that mtDNA homeostasis is impaired in the substantia nigra of individuals with PD.