Mitochondrial precursor signal peptide induces a unique permeability transition and release of cytochrome c from liver and brain mitochondria

This study tested the hypothesis that mitochondrial precursor targeting pep tides can elicit the release of cytochrome c from both liver and brain mito chondria by a mechanism distinct from that mediated by the classical, Ca2+- activated permeability transition pore. Human cytochrome oxidase subunit IV signal peptide (hCOXIV(1.22)) at concentrations from 15 to 100 muM induced swelling, a decrease in membrane potential, and cytochrome c release in bo th types of mitochondria, Although cyclosporin A and bongkrekic acid were w ithout effect, dibucaine, propanolol, dextran, and the uncoupler FCCP were each able to inhibit signal peptide-induced swelling and cytochrome c relea se. Adenylate kinase was coreleased with cytochrome c, arguing against a si gnal peptide-induced cytochrome c-specific pathway of efflux across the out er membrane. Taken together, the data indicate that a human mitochondrial s ignal peptide can evoke the release of cytochrome c from both liver and bra in mitochondria by a unique permeability transition that differs in several characteristics from the classical mitochondrial permeability transition. (C) 2001 Academic Press.