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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / pharmacology
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Adenylate Kinase / metabolism
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Animals
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Brain / cytology*
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Cytochrome c Group / metabolism*
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Dextrans / pharmacology
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Dibucaine / pharmacology
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Dose-Response Relationship, Drug
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Electron Transport Complex IV / chemistry
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Humans
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Ion Channels*
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Magnesium / pharmacology
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Membrane Potentials / drug effects
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / metabolism
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Mitochondria / drug effects*
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Mitochondria / enzymology
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Mitochondria / metabolism
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Mitochondria, Liver / drug effects*
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Mitochondria, Liver / enzymology
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Mitochondria, Liver / metabolism
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Mitochondrial Swelling / drug effects
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Permeability / drug effects
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Propranolol / pharmacology
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Protein Precursors / chemistry
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Protein Precursors / pharmacology*
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Protein Sorting Signals / physiology*
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Protein Transport / drug effects
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Rats
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Uncoupling Agents / pharmacology
Substances
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Cytochrome c Group
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Dextrans
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Ion Channels
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Membrane Proteins
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Protein Precursors
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Protein Sorting Signals
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Uncoupling Agents
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Adenosine Triphosphate
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Propranolol
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Electron Transport Complex IV
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Adenylate Kinase
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Magnesium
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Dibucaine