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This dissertation, The Role of Human Sodium Dicarboxylate Cotransporter in Oxidative Stress by Kwok-ho, Alvin, Cheung, 張國豪, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of the thesis entitled THE ROLE OF HUMAN SODIUM DICARBOXYLATE COTRANSPORTER IN OXIDATIVE STRESS Submitted by Alvin, Kwok Ho Cheung For the degree of Master of philosophy at the University of Hong Kong In August, 2003 Ageing is a genetically controlled process that can be modulated in the invertebrates by single gene mutations. An insertional mutation of Indy (I'm not dead yet) gene in Drosophila melanogaster resulted in a 50% increase in their maximal life-span. Here we show that an increased uptake of Krebs cycle intermediates in Chinese Hamster Ovary (CHO) cells which have a high endogenous expression of Sodium Dicarboxylate Cotransporter-1 (NaDC-1), a homolog of Indy gene in eukaryotes, resulted in the increase in oxidative stress. A respiratory chain inhibitor, rotenone reduced both glucose- and succinate-induced oxidative stress, indicating that reactive oxygen free radicals derived from these two substrates are generated from the mitochondrial electron transport chain. Lithium ion, which is known to be able to reduce the uptake of Krebs cycle intermediates, only reduced succinate-induced oxidative stress but not glucose-induced one. This suggests that the increased uptake of Krebs cycle intermediates lead to the increase in oxidative stress. This was confirmed by over-expressing human NaDC-1 in EcR (Ecdysone receptor) 293 cells, that has a very low level of endogenous NaDC-1 expression. EcR 293 cells over-expressing hNaDC-1 showed a higher level of succinate-induced oxidative stress. We propose that blocking the uptake activity of NaDC-1 can reduce oxidative stress. Since Li is able to interfere with other sodium-dependent transporters, we set off to screen for inhibitors specific for hNaDC-1. We identified a molecule called compound X that reversibly inhibits dicarboxylate uptake by hNaDC-1 and reduces succinate-induced oxidative stress. Our present studies indicate that an increased uptake of Krebs cycle intermediates increases oxidative stress, and the lowering of the transport activity of NaDC-1 reduces the oxidative stress. This may be at least one molecular mechanism involved in the life-span prolonging effect of Indy mutations in Drosophila. Thus, inhibitors of NaDC-1 may be a pharmacological agent to extend the life-span in mammals. (304 words) DOI: 10.5353/th_b2776907 Subjects: Oxidative stressCarrier proteinsKrebs cycleHamsters - Genetics

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