Involvement of mTORCs in premature cell senescence induced by aminooxyacetate inhibition of mitochondrial malate-aspartate shuttle
Date Issued
2008
Date
2008
Author(s)
Fan, Jhen-jia
Abstract
It is known that mitochondria play an important role in organism aging, such as free radical damage theory. Mitochondria also play a critical role in integrating nutrient information and metabolic activity during cell growth. In order to study the mitochondrial role in cell senescence, we refer to mitochondria as a nutrient sensor in pancreatic β cells, and have established a cell senescence system induced by aminooxyacetate (AOA) inhibition of mitochondrial malate-aspartate shuttle in normal human embryonic lung fibroblasts WI38, and we showed that α-ketoglutarate (αKG) blocked AOA-induced cell senescence. n this study, we further demonstrate that non-essential amino acid (NEAA) also blocked the AOA-induced cell senescence, but the cells still displayed an atypical (non-spreading) senescent morphology. This premature senescence is related to mitochondrial function, and independent of peroxide production. Interestingly, we observed that AOA treatment resulted in a dramatic reduction of mTORC1 activity, and the simultaneous appearance of mTORC2 hyperactivity. αKG blocked the AOA-induced imbalance of mTORC1 and mTORC2 activity. Although similar effect as αKG blockade, NEAA effect on mTORC1 and mTORC2 was relatively weaker. We also observed mTOR predominantly localized in the cytoplasm under AOA treatment. Decreasing αKG could lead to inactivation of the αKG-dependent dioxygenases, including PHD (prolyl-4-hydroxylase-domain protein). PHD regulates the stabilization of HIF-1αand promotes cell growth in the fly. Because αKG blocks AOA effect, we speculated that AOA-induced cell senescence was resulted from mitochondrial αKG insufficiency that subsequently inhibited the positive role of the hydroxylase in cell growth cycle, and eventually led to cell senescence. aken together, our results demonstrate αKG and NEAA blocked AOA-induced senescence and relative activity shift between mTORC1 and mTORC2 in normal human embryonic fibroblasts. This suggests that mitochondria could control cell growth cycle via regulation of mTORCs activity, and this could be the key that trigger cell senescence. Furthermore, our studies provide a normal viewpoint regarding mitochondrial role in organism aging besides the theory of accumulation of free radical-induced damage.
Subjects
AOA
mTOR
αKG- and Fe(II)-dependent dioxygenases
mitochondria
cell growth cycle
nutrient sensing
premature cell senescence
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