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Origin and functional consequences of the complex I defect in Parkinson's disease
Author(s) -
Swerdlow Russell H.,
Parks Janice K.,
Miller Scott W.,
Davis Robert E.,
Tuttle Jeremy B.,
Trimmer Patricia A.,
Sheehan Jason P.,
Bennett James P.,
Parker W. Davis
Publication year - 1996
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410400417
Subject(s) - neurodegeneration , mitochondrion , mitochondrial dna , biology , programmed cell death , reactive oxygen species , dna damage , apoptosis , microbiology and biotechnology , electron transport complex i , cell culture , dna , biochemistry , genetics , gene , disease , medicine , pathology , respiratory chain
The mitochondrial electron transport enzyme NADH: ubiquinone oxidoreductase (complex I), which is encoded by both mitochondrial DNA and nuclear DNA, is defective in multiple tissues in persons with Parkinson's disease (PD). The origin of this lesion and its role in the neurodegeneration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental toxins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastoma cells containing no mitochondrial DNA was repopulated with mitochondria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were assayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1‐methyl‐4‐phenyl pyridinium (MPP+). In PD cybrids we found a stable 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to 1‐methyl‐4‐phenyl pyridinium‐induced programmed cell death. The complex I defect in PD appears to be genetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species production and conferring increased neuronal susceptibility to mitochondrial toxins.