The effects of
1-methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine (2'Et-MPTP), 1-methyl-4-(2'-ethylphenyl)pyridinium (2'Et-MPP+), and the classic complex 1 inhibitor,
rotenone, on toxicity as well as on rates of
glucose use and
lactate production were studied using the
pheochromocytoma PC12 cell line. PC12 cells are neoplastic in nature and have a high rate of glycolysis accompanied by a large production of
lactate and a low use of
glucose carbon through the Krebs cycle.
1-Methyl-4-phenylpyridinium (MPP+) and analogues such
as 2'Et-MPP+ are actively accumulated by mitochondrial preparations in vitro and block
NADH dehydrogenase of complex 1. This blockade results in biochemical sequelae that are ultimately cytotoxic. In this study, untreated PC12 cells used
glucose and concomitantly accumulated
lactate in a time-dependent manner at all concentrations of
glucose studied. Treatment with 50 microM 2'Et-MPP+ or 50 nM
rotenone increased both rates significantly, indicating a shift toward increased glycolysis. Cell death caused by the
neurotoxins was also time and concentration dependent and markedly enhanced by
glucose depletion in the medium. The increase in 2'Et-MPTP-induced toxicity in low
glucose-supplemented cells was not due to an increase in pyridinium formation from the
tetrahydropyridine, but rather to the lack of
glucose for glycolysis. Moreover, inhibition of glycolysis with
2-deoxyglucose or
iodoacetic acid also enhanced the lethality of the
neurotoxins to the cells. The data in this study provide additional support to the hypothesis that 2'Et-MPP+ or related analogues act to kill cells by inhibiting mitochondrial respiration.(ABSTRACT TRUNCATED AT 250 WORDS)