Abstract
Mammalian cells adapt to different environmental conditions and alter cellular metabolic pathways to meet the energy demand for survival. Thus, the metabolic regulation of cells under special conditions, such as hypoxia, should be precisely regulated. During the metabolic regulation, mammalian target of rapamycin (mTOR) plays a vital role in the sensing of extracellular stimulations and regulating intracellular adaptations. Here, we report that mTOR complex 1 (mTORC1) signalling is a central regulator of lipid homoeostasis in lymphocytes. In hypoxia, mTORC1 activity is reduced and shifts lipid synthesis to lipid oxidation. Moreover, knockdown tuberous sclerosis complex 1 (TSC1) constitutively activates mTORC1 activity and impairs the hypoxia-induced metabolic shift. Therefore, TSC1 knockdown enhances hypoxia-induced cell death. Re-inactivation of mTORC1 activity via rapamycin may resist hypoxia-induced cell death in TSC1 knockdown lymphocytes. Our findings provide a deep insight into mTORC1 in the metabolic balance of lipid synthesis and oxidation, and imply that mTORC1 activity should be precisely regulated for the lipid homoeostasis in lymphocytes.
Highlights
IntroductionEnergy metabolism needs to be precisely regulated [1]
In mammalian cells, energy metabolism needs to be precisely regulated [1]
Biochemical results showed that protein levels of markers of mTOR complex 1 (mTORC1) signalling were all decreased in hypoxia, which was consistent with the previous report [20] (Figure 1B)
Summary
Energy metabolism needs to be precisely regulated [1]. Cells may rely on different catabolic metabolisms and generate their ATP from various pathways. Under some special conditions, such as hypoxia, cells develop multiple mechanisms for adaptation to lower oxygen levels [3]. Cells decrease their mitochondrial oxygen consumption for survival [4]. The anabolic lipid synthesis (lipogenesis) shifts to catabolic lipid oxidation, to meet the energy demand for energy production and cell survival [6]. The balance of lipid anabolism and catabolism should be tightly regulated and disruption of the adaptative metabolic shift may cause cell death and other diseases
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