Mitochondrial respiratory dysfunction and mutations in mitochondrial DNA in PINK1 familial parkinsonism.

A summary is presented of the cellular function and topology of the protein products of genes whose mutations are associated with familial forms of parkinsonism, with particular emphasis on mitochondrial involvement. Observations are reviewed which show mitochondrial respiratory depression in the fibroblasts of a patient affected by familial parkinsonism associated with homozygous PINK1 mutation. The respiratory depression, which was due to loss of mitochondrial cytochrome c, was associated with decreased capacity of respiratory chain oxidative phosphorylation and enhanced cellular level of ROS. Sequence analysis of the overall mtDNA revealed coexistence with the PINK1 mutation of homoplasmic point mutations in the ND5 and ND6 genes of complex I. The presence of these mutations appears to have an impact on the development of the parkinsonism, which can also occur in the heterozygous PINK1 mutation state.