The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease

Abstract

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.

Keywords: Alzheimer’s disease; Mitochondria; Neurodegeneration; Parkinson’s disease; Pathogenesis.

Fig. 1

Mitochondrial dysfunction in Alzheimer’s disease. The figure summarizes the main mitochondria-related mechanisms which have been proposed to he involved in the pathogenesis of AD. A defective mitochondrial functioning is supported hy various findings, including altered mitochondrial morphology and reduced glucose and oxygen consumption in patients’ hrains. An impairment of respiratory chain activity, in particular complex IV, has been detected in the disease. Extracellular Aβ and intracellular tau protein accumulation, prominent neuropathological findings in AD, have been proposed to he bi-directionally finked to mitochondrial dysfunction. Mitochondrial DNA alterations have also been detected in the disease

Fig. 2

Mitochondrial dysfunction in Parkinson’s disease. The figure summarizes the main mitochondria-related mechanisms which have been proposed to he involved in the pathogenesis of PD. Respiratory chain activity (in particular complex I) is dysfunctional in the disease and mitochondrial inhibitors (MPTP and rotenone) cause clinical and neuropathological parkinsonian features. Intracellular alpha-synuclein accumulation is bi-directionally finked to mitochondrial dysfunction. Alterations of mitochondrial DNA, including depletion, deletions, point mutations and impaired maintenance, have been described. Mitophagy is also involved in the disease, as supported by rare familial PD cases due to mutations in Parkin and PINK1

Fig. 3

Anomalous protein accumulation and mitochondrial dysfunction are involved in the pathogenesis of neurodegenerative diseases. Both genetic and environmental factors are implicated and aging plays a role as well. Although the identification of the initial causative mechanism is still a matter of dehate, it is interesting to observe that mitochondrial dysfunction triggers anomalous protein accumulation and, vice versa, anomalous protein accumulation contributes to mitochondrial dysfimction. Therefore, it is suggestive to hypothesize that whatever the initial causative mechanism is, once the neurodegenerative process has started, mitochondrial dysfunction and anomalous protein accumulation form a self-propagating loop which contributes to the maintenance and progression of the disease