Altered calcium homeostasis in cells transformed by mitochondria from individuals with Parkinson's disease.
Parkinson's disease may be linked to defects in mitochondrial function. Mitochondrially transformed cells (cybrids) were created from Parkinson's disease patients or disease-free controls. Parkinson's disease cybrids had 26% less complex I activity, but maintained comparable basal calcium and energy levels. Parkinson's disease cybrids recovered from a carbachol-induced increase in cytosolic calcium 53% more slowly than controls even with lanthanum and thapsigargin blockade. Inhibition of complex I with the Parkinson's disease-inducing metabolite 1-methyl-4-phenylpyridinium (MPP+) similarly reduced the rate of recovery after carbachol. This MPP(+)-induced reduction in recovery rates was much more pronounced in control cybrids than in Parkinson's disease cybrids. Parkinson's disease cybrids had less carbonyl cyanide m-chlorophenylhydrazone-releasable calcium. Bypassing complex I with succinate partially restored Parkinson's disease cybrid, and MPP+ suppressed control cybrid recovery rates. The subtle alteration in calcium homeostasis of Parkinson's disease cybrids may reflect an increased susceptibility to cell death under circumstances not ordinarily toxic.
Sheehan
J P
JP
Department of Neurological Surgery, University of Virginia, Charlottesville 22908, USA.
Swerdlow
R H
RH
Parker
W D
WD
Miller
S W
SW
Davis
R E
RE
Tuttle
J B
JB
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000502:physiology; D004734:Energy Metabolism; D005260:Female; D006706:Homeostasis; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D015259:Dopamine Agents; D007476:Ionophores; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium