title: Mitochondrial precursor signal peptide induces a unique permeability transition and release of cytochrome c from liver and brain mitochondria.
abstract: This study tested the hypothesis that mitochondrial precursor targeting peptides can elicit the release of cytochrome c from both liver and brain mitochondria by a mechanism distinct from that mediated by the classical, Ca2+-activated permeability transition pore. Human cytochrome oxidase subunit IV signal peptide (hCOXIV1-22) at concentrations from 15 to 100 microM induced swelling, a decrease in membrane potential, and cytochrome c release in both types of mitochondria. Although cyclosporin A and bongkrekic acid were without effect, dibucaine, propanolol, dextran, and the uncoupler FCCP were each able to inhibit signal peptide-induced swelling and cytochrome c release. Adenylate kinase was coreleased with cytochrome c, arguing against a signal peptide-induced cytochrome c-specific pathway of efflux across the outer membrane. Taken together, the data indicate that a human mitochondrial signal peptide can evoke the release of cytochrome c from both liver and brain mitochondria by a unique permeability transition that differs in several characteristics from the classical mitochondrial permeability transition.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: Y E
authors.initials: YE
authors.lastname: Kushnareva
authors.forename: B M
authors.initials: BM
authors.lastname: Polster
authors.forename: P M
authors.initials: PM
authors.lastname: Sokolove
authors.forename: K W
authors.initials: KW
authors.lastname: Kinnally
authors.forename: G
authors.initials: G
authors.lastname: Fiskum
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology*; D003574:Cytochrome c Group / Q000378:metabolism*; D003911:Dextrans / Q000494:pharmacology; D003992:Dibucaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000737:chemistry; D006801:Humans; D007473:Ion Channels; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D011498:Protein Precursors / Q000737:chemistry / Q000494:pharmacology*; D021382:Protein Sorting Signals / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D003574:Cytochrome c Group; D003911:Dextrans; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011498:Protein Precursors; D021382:Protein Sorting Signals; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D011433:Propranolol; D003576:Electron Transport Complex IV; D000263:Adenylate Kinase; D008274:Magnesium; D003992:Dibucaine