Journal
BIOCHEMICAL JOURNAL
Volume 413, Issue -, Pages 323-332Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20080321
Keywords
carboxyatractylate (CAtr); 4-hydroxynonenal (HNE); proton leak; rat liver mitochondrion; trypsin
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Funding
- Medical Research Council [MC_U105663137] Funding Source: Medline
- Wellcome Trust [065326/Z/01/Z, 066750/B/01/Z] Funding Source: Medline
- MRC [MC_U105663137] Funding Source: UKRI
- Medical Research Council [MC_U105663137] Funding Source: researchfish
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Mitochondria generate reactive oxygen species, whose downstream lipid peroxidation products, such as 4-hydroxythonenal, 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 carboxy-atractylate, 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.
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