Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, Heilongjiang Province, China; Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, Ministry of Health (23618504), Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
Sci Total Environ. 2022 Aug 25;836:155691. doi: 10.1016/j.scitotenv.2022.155691. Epub 2022 May 4.
Exposure to inorganic or organic arsenic compounds continues to pose substantial public health concerns for hundreds of millions of people around the globe. Highly exposed individuals are susceptible to various illnesses, including impairments and cancers of the lung, liver, skin and bladder. Long-term exposure to low-dose arsenic has been identified to induce aerobic glycolysis, which contributes to cells aberrant proliferation. However, the mechanism underlying arsenic-induced aerobic glycolysis is still unclear. Here, mtDNA copy number is enhanced in arsenic-exposed populations and a positive correlation between serum HK2 and urinary total arsenic was observed in the individuals with high urine arsenic (≥ 0.032 mg/L). In a rat model of trivalent arsenic (iAs) exposure, the levels of HK2, NDUFA9 and NDUFB8 were increased in the rats treated with iAs daily by gavage for 12 weeks than those in the control rats. Subsequently, in a low-dose arsenic exposure cell model we found that 0.2 μmol/L iAs induced aerobic glycolysis to promote L-02 cells proliferation and inhibit apoptosis, in which HK2 played an important role. Further studies showed accumulated ROS determined the metabolic reprogramming via activating AKT and then increasing HK2 expression. On the one hand, activated AKT induced aerobic glycolysis by increasing HK2 to promote L-02 cells viability and DNA synthesis; on the other hand, phosphorylated AKT induced HK2 mitochondrial outer-membrane location with VDAC1 to inhibit apoptosis. Taken together, our results indicated that ROS induced by low-dose arsenic exposure determined energy metabolic reprogramming and acted a critical regulator for AKT-dependent HK2 expression and aerobic glycolysis.
暴露于无机或有机砷化合物仍然对全球数亿人构成重大公共健康问题。高度暴露的个体易患各种疾病，包括肺、肝、皮肤和膀胱的损伤和癌症。长期低剂量砷暴露已被确定会诱导有氧糖酵解，这有助于细胞异常增殖。然而，砷诱导的有氧糖酵解的机制仍不清楚。在这里，暴露于砷的人群中线粒体 DNA 拷贝数增加，并且在尿液中总砷含量高（≥ 0.032mg/L）的个体中观察到血清 HK2 与尿总砷之间存在正相关。在三价砷（iAs）暴露的大鼠模型中，通过灌胃每天用 iAs 处理 12 周的大鼠中 HK2、NDUFA9 和 NDUFB8 的水平高于对照组大鼠。随后，在低剂量砷暴露细胞模型中，我们发现 0.2μmol/L 的 iAs 诱导有氧糖酵解以促进 L-02 细胞增殖并抑制细胞凋亡，其中 HK2 起重要作用。进一步的研究表明，积累的 ROS 通过激活 AKT 并增加 HK2 表达来决定代谢重编程。一方面，激活的 AKT 通过增加 HK2 来诱导有氧糖酵解，从而促进 L-02 细胞活力和 DNA 合成；另一方面，磷酸化的 AKT 诱导 HK2 在线粒体膜上的位置与 VDAC1 结合以抑制细胞凋亡。总之，我们的结果表明，低剂量砷暴露引起的 ROS 决定了能量代谢重编程，并作为 AKT 依赖性 HK2 表达和有氧糖酵解的关键调节剂。
