Ca 2þ in the mitochondrial matrix regulates several physiological processes, from ATP synthesis to cell death. Most mitochondrial Ca 2þ uptake occurs through the mitochondrial Ca 2þ uniporter, a highly-selective ion channel embedded in the inner membrane. We recently demonstrated that both Ca 2þ uptake and uniporter channel activity are increased in a mouse model of mitochondrial cardiomyopathies. In these diseases, which primarily present in infants and children, characteristic deficits in oxidative phosphorylation produce a signal that boosts mitochondrial Ca 2þ levels. Here we investigated the mechanism for such enhancement. By selective pharmacological inhibition of individual electron transport chain complexes, we found that rotenone-induced complex I dysfunction increases mitochondrial Ca 2þ uptake. Since Ca 2þ transport is governed by both uniporter activity and the transmembrane voltage gradient (DJ), we measured uniporter activity directly using whole-mitoplast patch-clamp. HEK293T cells were incubated with 0.1, 0.3 and 1 mM rotenone for 72 hr to chronically inhibit complex I. After such inhibition, we found that uniporter current density increased from À72 5 6 pA/pF for control mitoplasts (0 nM rotenone) to À90 5 6 pA/pF in 0.3 mM rotenone and À130 5 20 pA/pF in 1 mM rotenone. Such an increase was not due to acute effects of rotenone on the uniporter channel itself, as it did not affect or only mildly inhibited current densities at these concentrations. Our data indicate that chronic inhibition of complex I produces a signal that increases the activity of MCU.
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