Stimulation of mitochondrial proton conductance by hydroxynonenal requires a high membrane potential
Résumé
Mild uncoupling of oxidative phosphorylation, caused by a leak of protons back into the matrix, limits mitochondrial production of reactive oxygen species. This proton leak can be induced by lipid peroxidation products of reactive oxygen species, such as 4-hydroxynonenal (HNE). HNE activates uncoupling proteins (UCP1, UCP2 and UCP3) and the adenine nucleotide translocase, thereby providing a negative feedback loop. The mechanism of activation and the conditions necessary to induce uncoupling by HNE are unclear. We find that activation of proton leak by HNE in rat and mouse skeletal muscle mitochondria is dependent upon incubation with respiratory substrate. In the presence of HNE, mitochondria energised with succinate become progressively more leaky to protons over time compared to mitochondria in the absence of either HNE or succinate. Energised mitochondria must attain a high membrane potential to allow HNE to activate uncoupling; a drop of 10 – 20 mV from the resting value is sufficient to blunt induction of proton leak by HNE. Uncoupling occurs through UCP3 (11%), adenine nucleotide translocase (64%) and other pathways (25%). Our findings show that exogenous HNE only activates uncoupling at high membrane potential. They suggest that both endogenous HNE production and high membrane potential are required before mild uncoupling will be triggered to attenuate mitochondrial ROS production
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