The Inducible Senescence Mechanism of Human Fibroblast WI38 by Transaminase Inhibitor aminooxyacetic acid
Date Issued
2005
Date
2005
Author(s)
Lee, Chun-Sheng
DOI
zh-TW
Abstract
Mitochondria, as a cellular energy factory mediates energy production and metabolic pathway regulation. Mitochondria dysfunction also affects the fate of cell, such as cellular senescence or apoptosis. Aminooxyacetic acid (AOA), a potent inhibitor of the mitochondrial malate-aspartate shuttle, causes cellular energy depletion by inhibiting the transfer of NADH reducing potential produced by glycolysis to mitochondria.
This study, we provide the evidence that AOA can induce senescence in normal human fibroblast WI38. By treating with 2.5mM AOA, cellular senescence reached to 73.8% at the sixth day; in contrast, the same treatment could not induce cellular senescence in osteoblastoma U2OS cells, which lacks p16 and ARF. In addition to morphological phenotype, there is accumulation of p53, p16, p21 and retinoblastoma protein (Rb) is at the state of cell cycle arrest. Also, we observed the ratio of [AMP]/ [ATP] increased indicating a change of energy. It also reflects on the TOR and S6K signaling pathway.
The mechanism of AOA induction of senescence may involve two pathways：One may act through the imbalance of non-essential amino acid; the other may through the energy state of mitochondria. For the former hypothesis, we tried to reverse the senescence by supplementing non-essential amino acid; however, no obvious effect. Then, we succeeded in reversing the AOA-induced senescence by co-treatment with 2-oxoglutarate (2-OG), the intermediate of TCA cycle, and co-treatment with Fe2+ chelator DFO abolished such reversion. In addition, chemicals inhibiting HIF-1α proline hydroxylation also induce senescence. Take together, this study indicates that AOA-induced senescence may mediate through the 2-OG and the HIF-1α pathway.
Subjects
細胞老化
AOA
senescence
Type
other
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