The role of respiratory chain complex I deficiency and free radicals in neurodegenerative disease

Severe defects of complex I of the respiratory chain cause a range of lethal childhood diseases, but milder complex I defects have been found in patients with Parkinson disease, and complex I inhibitors have been used to create an animal model of Parkinson`s disease. Respiratory chain defects decrease the cellular ability to generate ATP, but the accumulation of highly reduced intermediates can also cause damage due to increased rates of free radical generation. Cellular responses to free radicals (such as apoptosis) may be even more important than ATP depletion in disease pathology. The project will focus initially on the collection of cell lines with severe defects of respiratory chain complex I, aiming to determine: 1. what types and rates of free radicals accumulate, and 2. the effects on free radical scavenging systems in cell lines from patients with nuclear or mitochondrial DNA encoded defects of complex I. Characterising the effects of severe complex I deficiency on free radical generation and scavenging systerms should serve as a model and prelude for studies in Parkinson disease, where the putative complex I defects are milder, and Friedreich`s ataxia, where recent findings suggest that Frataxin is probably involved in mitochondrial iron transport and thus in free radical generation.