The Blocking Mechanism of Anaplerosis pathway on AOA induced Cellular Senescence
Date Issued
2010
Date
2010
Author(s)
Su, Shou-Yi
Abstract
Cell proliferation is the process of cell self-replication, and the most important principle of self-replication is fidelity. During cell self-replicating process, cells will be continuously monitored for its fidelity. When cells are challenged with intrinsic or extrinsic environment changes, the self-replicating fidelity will no longer be guaranteed. Then, cell cycle arrests until the fidelity is again ensured. If cell senses fidelity being challenged, the cell will enter apoptosis or cellular senescence process to avoid enlargement the loss of fidelity.
Cell proliferation is driven by cell growth. Proliferating cells often take up nutrients in excess of bioenergetic needs and shunt metabolites into pathways that support a platform for biosynthesis. In order to rapidly accumulate biomass, cell must engage in the metabolic reprogramming. Mitochondria play a crucial role in cell growth. When metabolic reprogram proceeds, mitochondria will switch the role of TCA cycle from producing energy to exporting much of the intermediates for biomass synthesis. The fidelity checking during cell growth process lies in the dynamic complex metabolic pathways. When the metabolic flow is blocked. Cell growth fidelity will not be guaranteed.
In human embryonic fibroblast WI38 cell system, the malate-aspartate shuttle inhibitor, AOA (aminooxyacetate), impeded the metabolic flow and induced cell cycle arrest and senescence, and changed cell the growth center (mTOR) activity balance. These AOA-induced effects were blocked by co-treatment with NEAA (non-essential amino acid), α-ketoglutarate, aspartate, pyruvate or oxaloacetate. The molecular mechanism of this AOA effect remains to be explored to gain further insight into the interaction between metabolic flow and cell growth.
In this study, we explore the important role of mitochondria in reprogramming the metabolic pathway and controlling the cell growth fidelity.
Subjects
mitochondria
metabolic reprogram
fidelity
cellular senescence
Type
thesis
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