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J. Biol. Chem., Vol. 269, Issue 20, 14546-14552, May, 1994

Role of mitochondrial Ca2+ in the oxidative stress-induced dissipation of the mitochondrial membrane potential. Studies in isolated proximal tubular cells using the nephrotoxin 1,2-dichlorovinyl-L-cysteine

B van de Water, JP Zoeteweij, HJ de Bont, GJ Mulder and JF Nagelkerke
Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, The Netherlands.

The relationship between mitochondrial Ca2+, oxidative stress, and a dissipation of the mitochondrial membrane potential (delta psi) was investigated in proximal tubular kidney cells. Freshly isolated proximal tubular cells from rat kidney were exposed to the nephrotoxin 1,2-dichlorovinyl-L-cysteine (DCVC). DCVC stimulated the formation of hydroperoxides as determined by flow cytometry using the hydroperoxide- sensitive compound dichlorofluorescein. This was prevented by the antioxidant diphenylphenylenediamine (DPPD) and the iron chelator desferrioxamine. Studies in individual cells with video-intensified fluorescence microscopy showed that a DCVC-induced increase in the intracellular free calcium concentration ([Ca2+]i) was accompanied by an increase in the mitochondrial free calcium concentration ([Ca2+]m). The latter increase was selectively prevented by an inhibitor of the mitochondrial calcium uniporter, ruthenium red (RR). Chelation of cellular Ca2+ with EGTA acetoxymethyl ester (EGTA/AM) completely prevented the formation of hydroperoxides, whereas inhibition of the uptake of Ca2+ by the mitochondria with RR reduced it. This indicates that the increase in [Ca2+]m is important for the induction of oxidative stress by DCVC. DPPD and desferrioxamine did not protect against a DCVC-induced increase in [Ca2+]i and [Ca2+]m, indicating that oxidative stress is the consequence rather than the cause of the cellular calcium perturbations. DCVC decreased delta psi and caused cell death; both effects were clearly delayed by EGTA/AM and RR, although they could not prevent a decrease in delta psi. The latter decrease was completely prevented by inhibition of the beta-lyase- mediated metabolism of DCVC with aminooxyacetic acid. Like EGTA/AM, inhibition of oxidative stress with DPPD and desferrioxamine delayed the decrease in delta psi. This strongly suggests that the decrease in delta psi caused by metabolites of DCVC directly is potentiated by Ca(2+)-dependent DCVC-induced hydroperoxide formation. The importance of both hydroperoxide formation and mitochondrial damage in DCVC- induced cell killing is discussed.
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