Calpain-mediated MPP+ toxicity in mitochondrial DNA depleted cells.
MPP+ (1-methyl-4-phenylpyridium ion), a complex I - inhibiting metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes anatomic-specific neurodegeneration. To evaluate the broader role of mitochondria in MPP+-induced cell death, we exposed neuron-like NT2 human teratocarcinoma cells with mtDNA rho+ and without mtDNA (rho0) to MPP+. MPP+ minimized the ability of both rho+ and rho0 cells to reduce MTT. Only rho+ cells, though, initiated intrinsic pathway-mediated apoptosis. MPP+ also activated calpains in both rho+ and rho0 cell lines. The calpain inhibitor MDL 28710 was able to prevent the MPP+-related MTT reduction change in rho0 but not rho+ cells. We conclude that 1) MPP+-induced apoptosis requires functional mitochondria, 2) MPP+ activates calpains independent of respiratory chain inhibition, and 3) calpain activation mediates some aspects of MPP+ toxicity.
Domingues
A Filipa
AF
Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Esteves
A Raquel F
AR
Swerdlow
Russell H
RH
Oliveira
Catarina R
CR
Cardoso
Sandra M
SM
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018243:Teratocarcinoma
D004272:DNA, Mitochondrial; D002154:Calpain; D020169:Caspases; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium