Abnormal mitochondrial morphology in sporadic Parkinson's and Alzheimer's disease cybrid cell lines

Diseases linked to defective mitochondrial function are characterized by mo rphologically abnormal, swollen mitochondria with distorted cristae. Severa l lines of evidence now suggest that sporadic forms of Parkinson's disease (PD) and Alzheimer's disease (AD) are linked to mitochondrial dysfunction a rising from defects in mitochondrial DNA (mtDNA). Human neuroblastoma (SH-S Y5Y) cells that are deficient in mtDNA (Rho(0)) were repopulated with mitoc hondria from AD or PD patients or age-matched controls. These cytoplasmic h ybrid (cybrid) cell lines differ only in the source of their mtDNA. Differe nces between cybrid cell lines therefore arise from differences in mtDNA an d provide a model for the study of how impaired mitochondrial function alte rs the mitochondria themselves and how these changes adversely affect the n euronal cells they occupy. Cybrid cell mitochondria were labeled with the m itochondrial membrane potential-sensitive dye, JC-1. Analysis of these JC-1 labeled mitochondria by confocal microscopy revealed that mitochondrial me mbrane potential was significantly reduced in both PD and AD cybrid cells w hen compared with controls. Ultrastructural examination showed that control cybrid cells contained small, morphologically normal, round or oval mitoch ondria with a dark matrix and regular distribution of cristae. PD cybrid ce lls contained a significant and increased percentage of mitochondria that w ere enlarged or swollen and had a pale matrix with few remaining cristae (0 .26-0.65 mu m(2)). AD cybrid cells also contained a significantly increased percentage of enlarged or swollen mitochondria (0.25-5.0 mu m(2)) that had a pale matrix and few remaining cristae. Other pathological features such as crystallike intramitochondrial inclusions and cytoplasmic inclusion bodi es mere also found in PD and AD cybrids. These observations suggest that tr ansfer of PD or AD mtDNA into Rho(0) cells was sufficient to produce pathol ogical changes in mitochondrial ultrastructure that are similar to those se en in other mitochondrial disorders. These data were reported in abstract f orm (Trimmer et al., 1998, Soc. Neurosci. Abstr. 24: 476). (C) 2000 Academi c Press.