Calpain-mediated MPP+ toxicity in mitochondrial DNA depleted cells.

MPP+ (1-methyl-4-phenylpyridium ion), a complex I — inhibiting metabolite of 1-methyl-4-phe-nyl-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 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.