Title | High membrane potential promotes alkenal-induced mitochondrial uncoupling and influences adenine nucleotide translocase conformation. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Azzu, V, Parker, N, Brand, MD |
Journal | Biochem J |
Volume | 413 |
Issue | 2 |
Pagination | 323-32 |
Date Published | 2008 Jul 15 |
ISSN | 1470-8728 |
Keywords | Aldehydes, Animals, Biological Transport, Female, Kinetics, Membrane Potentials, Mitochondria, Mitochondria, Liver, Mitochondrial ADP, ATP Translocases, Nucleotides, Oxidative Phosphorylation, Oxygen Consumption, Protein Conformation, Protons, Rats |
Abstract | Mitochondria generate reactive oxygen species, whose downstream lipid peroxidation products, such as 4-hydroxynonenal, induce uncoupling of oxidative phosphorylation by increasing proton leak through mitochondrial inner membrane proteins such as the uncoupling proteins and adenine nucleotide translocase. Using mitochondria from rat liver, which lack uncoupling proteins, in the present study we show that energization (specifically, high membrane potential) is required for 4-hydroxynonenal to activate proton conductance mediated by adenine nucleotide translocase. Prolonging the time at high membrane potential promotes greater uncoupling. 4-Hydroxynonenal-induced uncoupling via adenine nucleotide translocase is prevented but not readily reversed by addition of carboxyatractylate, suggesting a permanent change (such as adduct formation) that renders the translocase leaky to protons. In contrast with the irreversibility of proton conductance, carboxyatractylate added after 4-hydroxynonenal still inhibits nucleotide translocation, implying that the proton conductance and nucleotide translocation pathways are different. We propose a model to relate adenine nucleotide translocase conformation to proton conductance in the presence or absence of 4-hydroxynonenal and/or carboxyatractylate. |
DOI | 10.1042/BJ20080321 |
Alternate Journal | Biochem. J. |
Citation Key | 10.1042/BJ20080321 |
PubMed ID | 18426390 |
PubMed Central ID | PMC2474560 |
Grant List | MC_U105663137 / / Medical Research Council / United Kingdom 066750/B/01/Z / / Wellcome Trust / United Kingdom 065326/Z/01/Z / / Wellcome Trust / United Kingdom |