Abstract
This paper reconsiders the role of mitochondria in aging and in Parkinson’s Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD.
Highlights
High energy requirements tissues such as the brain are highly dependent on mitochondria.Mitochondria are intracellular organelles deriving and storing energy through the respiratory chain by oxidative phosphorylation [1,2]
Both in substantia nigra (SN) neurons of aged subjects and of subjects with Parkinson’s Disease (PD), the load of mitochondrial DNA (mtDNA) mutations paralleled the deficiency of the respiratory chain, which suggests that a common cell mechanism is at play in the two conditions
Popa-Wagner et al [62] have shown that the turnover rates for DMN1l and FIS1, which are proteins implicated in mitochondrial biogenesis, mitophagy, and fission go in opposite directions in the cerebellum of 22-month-old C57BL6j mice when compared to three-month-old mice
Summary
High energy requirements tissues such as the brain are highly dependent on mitochondria. Mitochondria have several copies of the mitochondrial genome that consists of a 16.5 kb circular DNA molecule [2,3] that, in turn, provides the template for 13 essential proteins of the respiratory chain. Heteroplasmic mtDNA mutations derive clonally from expansion of single mitochondria with a resulting normal and respiratory-deficient mitochondria mixture within the same cell. When compared to other neurons, SN dopaminergic neurons have more mtDNA deletions, which is shown by two independent studies [6,7] In these two studies, both in SN neurons of aged subjects and of subjects with PD, the load of mtDNA mutations paralleled the deficiency of the respiratory chain, which suggests that a common cell mechanism is at play in the two conditions
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