Complex I Deficiency

Abstract

Parkinson's disease (PD) is a complex disorder that results from the combined and interactive effects of multiple genetic and environmental factors. As our understanding of these diverse genetic and environmental influences increases, a convergence of data points towards an important role for mitochondrial dysfunction in PD. Complex I (CI) activity is impaired in the substantia nigra (SN) in PD, and toxins that inhibit CI reproduce some of the pathological features of PD. Indirect data implicate mitochondrial DNA (mtDNA) mutations as the origin of the CI defect, and studies are ongoing regarding the possible roles of inherited and somatic mtDNA mutations. Glutathione deficiency may also play a role. Mitochondrial dysfunction leads to increased free radical production and oxidative stress. Both mitochondrial dysfunction and oxidative stress are implicated in several genetic forms of PD, including alpha-synuclein mutations and autosomal recessive PD associated with mutations in DJ-1, Parkin or PINK1. Environmental factors such as pesticide exposure may also play a role. Understanding the origin and consequences of mitochondrial CI dysfunction in PD remains an important goal of current PD research, and may help in the search for neuroprotective therapies.