Mitochondrial Ca2+-induced Ca2+Release Mediated by the Ca2+Uniporter

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Abstract
We have reported that a population of chromaffin cell mitochondria takes up large amounts of Ca2+during cell stimulation. The present study focuses on the pathways for mitochondrial Ca2+efflux. Treatment with protonophores before cell stimulation abolished mitochondrial Ca2+uptake and increased the cytosolic [Ca2+] ([Ca2+]c) peak induced by the stimulus. Instead, when protonophores were added after cell stimulation, they did not modify [Ca2+]ckinetics and inhibited Ca2+release from Ca2+-loaded mitochondria. This effect was due to inhibition of mitochondrial Na+/Ca2+exchange, because blocking this system with CGP37157 produced no further effect. Increasing extramitochondrial [Ca2+]ctriggered fast Ca2+release from these depolarized Ca2+-loaded mitochondria, both in intact or permeabilized cells. These effects of protonophores were mimicked by valinomycin, but not by nigericin. The observed mitochondrial Ca2+-induced Ca2+release response was insensitive to cyclosporin A and CGP37157 but fully blocked by ruthenium red, suggesting that it may be mediated by reversal of the Ca2+uniporter. This novel kind of mitochondrial Ca2+-induced Ca2+release might contribute to Ca2+clearance from mitochondria that become depolarized during Ca2+overload.