Although the pathogenesis of
neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of
mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common
neurodegenerative disorders:
Alzheimer's disease (AD) and
Parkinson's disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced
glucose and
oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered
mitochondrial DNA. Furthermore,
amyloid pathology and
mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease.
Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between
alpha-synuclein accumulation and
mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular
multiple system atrophy. The available knowledge is still not sufficient to clearly state whether
mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.