Mitochondrial UCP4 attenuates MPP+- and dopamine-induced oxidative stress,mitochondrial depolarization,and ATP deficiency in neurons and is interlinked with UCP2 expression |
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Authors: | Andrew Chi-Yuen Chu Philip Wing-Lok Ho Ken Hon-Hung Kwok Jessica Wing-Man Ho Koon-Ho Chan Hui-Fang Liu Michelle Hiu-Wai Kung David Boyer Ramsden Shu-Leong Ho |
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Institution: | 1. Department of Animal Physiology and Development, Adam Mickiewicz University, Umultowska 89, 61–614 Poznan, Poland;2. Department of Bioenergetics, Adam Mickiewicz University, Umultowska 89, 61–614 Poznan, Poland;3. Institute for Environmental and Human Health Protection, University of Gdansk, Sobieskiego 18/19, 80–952 Gdansk, Poland;4. Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50–383 Wroclaw, Poland |
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Abstract: | Mitochondrial uncoupling proteins (UCPs) uncouple oxidative phosphorylation from ATP synthesis. We explored the neuroprotective role of UCP4 with its stable overexpression in SH-SY5Y cells, after exposure to either MPP+ or dopamine to induce ATP deficiency and oxidative stress. Cells overexpressing UCP4 proliferated faster in normal cultures and after exposure to MPP+ and dopamine. Differentiated UCP4-overexpressing cells survived better when exposed to MPP+ with decreased LDH release. Contrary to the mild uncoupling hypothesis, UCP4 overexpression resulted in increased absolute ATP levels (with ADP/ATP ratios similar to those of controls under normal conditions and ADP supplementation) associated with increased respiration rate. Under MPP+ toxicity, UCP4 overexpression preserved ATP levels and mitochondrial membrane potential (MMP) and reduced oxidative stress; the preserved ATP level was not due to increased glycolysis. Under MPP+ toxicity, the induction of UCP2 expression in vector controls was absent in UCP4-overexpressing cells, suggesting that UCP4 may compensate for UCP2 expression. UCP4 function does not seem to adhere to the mild uncoupling hypothesis in its neuroprotective mechanisms under oxidative stress and ATP deficiency. UCP4 overexpression increases cell survival by inducing oxidative phosphorylation, preserving ATP synthesis and MMP, and reducing oxidative stress. |
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