ABSTRACT
There has been a steady accumulation of data that point to a role for mitochondria in the pathogenesis of Parkinson’s disease (PD). In broad terms, it is evident that toxins that impair mitochondrial function produce lesions resembling PD in animals and humans, and that mitochondria may be a major source of reactive oxygen species (ROS) that could contribute to the oxidative damage evident in PD brains. It has also been suggested that there is a systemic impairment of mitochondrial function in patients with PD that extends beyond the central nervous system. In more specific terms, many of the proposed mechanisms that invoke mitochondrial dysfunction involve complex I of the electron transport chain, which is also known as the NADH: coenzyme Q oxidoreductase. A generous interpretation of these findings would lead to the conclusion that complex I impairment is the key early event in PD pathogenesis, and that this mechanism could initiate the loss of dopaminergic neurons that characterizes this disease. However, a more conservative interpretation raises a number of questions that need to be addressed before such conclusions can be considered reasonable. In particular, it is important to determine whether impaired complex I function is a characteristic of the disease, and also whether the proposed impairment can alter mitochondrial function in a manner that is mechanistically consistent with the putative consequence of excessive ROS production as a critical pathogenic event. Beyond these considerations, one must also evaluate the basis for any conclusions regarding ROS generation, because of the continuing evolution in experimental methods used in studies of mitochondrial function.
