The Reversal Effect of Amino Acids on Aminooxyacetate-induced Cellular Senescence
Date Issued
2009
Date
2009
Author(s)
Tsai, Meng-Jen
Abstract
Mitochondria play a crucial role in cell growth. The switching role ofitochondria TCA cycle from producing maximal amount of ATP to exporting muchf the intermediates for lipid, protein, and nucleic acid synthesis is the main part ofmetabolic reprogramming” process that necessary for cells to proliferate. This resultsn a continuous efflux of intermediates, which is so-called cataplerosis. In response toataplerosis, cells switch the generation of ATP from TCA cycle to glycolysis andnhance LDH-A activity to convert pyruvate into lactate and also maintain theAD+/NADH ratio, ensuring high glycolytic flux in proliferating cells. In order toustain TCA cycle function under cataplerosis, cells must re-supply TCA cyclentermediates, which is so-called anaplerosis. Anaplerosis is critical for cell growthecause it enables cells to use TCA cycle as a supply of biosynthetic precursors.lutamine metabolism is one of the anaplerotic sources. Proliferating cells metabolizelutamine into glutamate and then aKG, which is convenient for cells to use as carbonource for TCA cycle, providing anaplerosis sources in growing cells.n WI38 cells system, the malate-aspartate shuttle inhibitor, AOA, induces cellycle arrest and senescence with the reduction of mTORC1 and promotion ofTORC2 activity. These effects are blocked by co-treating aKG or NEAA. Theeversal effect of aKG on AOA treatment is believed as replenishing TCA cyclentermediates through anaplerosis pathway. On the other hand, after testing individualmino acid in NEAA, we discovered that only aspartate and asparagine can rescue theell cycle arrest and senescence ratio caused by AOA and the effect of aspartate isetter than asparagine. Aspartate may function through enhancing asparagineynthetase activity or as a competitor of AOA thus attenuating its effect. We also triedeucine because of its greatest effect on activating mTORC1. However, addition ofeucine has no effect to reverse AOA-induced cell cycle arrest and senescence.vn this study, we found that the function of malate-aspartate shuttle is importantor cell growth, implying that malate-aspartate shuttle is essential in anaplerosis. Thistudy also points out the importance of mitochondria switching role in metaboliceprogramming in cell growth.
Subjects
mitochondria
cell growth
metabolic reprogramming
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