Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL, 35294, USA.
Department of Pharmacology, Whiddon College of Medicine, University of South Alabama, 1660 Springhill Ave, Mobile, AL, 36604, USA.
Chem Biol Interact. 2024 May 1;394:110991. doi: 10.1016/j.cbi.2024.110991. Epub 2024 Apr 4.
Exogenous exposures to the triose sugar dihydroxyacetone (DHA) occur from sunless tanning products and electronic cigarette aerosol. Once inhaled or absorbed, DHA enters cells, is converted to dihydroxyacetone phosphate (DHAP), and incorporated into several metabolic pathways. Cytotoxic effects of DHA vary across the cell types depending on the metabolic needs of the cells, and differences in the generation of reactive oxygen species (ROS), cell cycle arrest, and mitochondrial dysfunction have been reported. We have shown that cytotoxic doses of DHA induced metabolic imbalances in glycolysis and oxidative phosphorylation in liver and kidney cell models. Here, we examine the dose-dependent effects of DHA on the rat cardiomyocyte cell line, H9c2. Cells begin to experience cytotoxic effects at low millimolar doses, but an increase in cell survival was observed at 2 mM DHA. We confirmed that 2 mM DHA increased cell survival compared to the low cytotoxic 1 mM dose and investigated the metabolic differences between these two low DHA doses. Exposure to 1 mM DHA showed changes in the cell's fuel utilization, mitochondrial reactive oxygen species (ROS), and transient changes in the glycolysis and mitochondrial energetics, which normalized 24 h after exposure. The 2 mM dose induced robust changes in mitochondrial flux through acetyl CoA and elevated expression of fatty acid synthase. Distinct from the 1 mM dose, the 2 mM exposure increased mitochondrial ROS and NAD(P)H levels, and sustained changes in LDHA/LDHB and acetyl CoA-associated enzymes were observed. Although the cells were exposed to low cytotoxic (1 mM) and non-cytotoxic (2 mM) acute doses of DHA, significant changes in mitochondrial metabolic pathways occurred. Further, the proliferation increase at the acute 2 mM DHA dose suggests a metabolic adaption occurred with sustained consequences in survival and proliferation. With increased exogenous exposure to DHA through e-cigarette aerosol, this work suggests cell metabolic changes induced by acute or potentially chronic exposures could impact cell function and survival.
外源性摄入三碳糖二羟丙酮(DHA)可来自于日光浴产品和电子烟气溶胶。一旦被吸入或吸收,DHA 进入细胞,转化为二羟丙酮磷酸盐(DHAP),并被整合到几种代谢途径中。DHA 的细胞毒性作用因细胞类型而异,取决于细胞的代谢需求,并且已经报道了活性氧(ROS)的产生、细胞周期停滞和线粒体功能障碍的差异。我们已经表明,DHA 的细胞毒性剂量会在肝和肾细胞模型中诱导糖酵解和氧化磷酸化的代谢失衡。在这里,我们检查了 DHA 对大鼠心肌细胞系 H9c2 的剂量依赖性影响。细胞在低毫摩尔剂量下开始出现细胞毒性作用,但在 2 mM DHA 时观察到细胞存活率增加。我们证实,与低细胞毒性的 1 mM DHA 剂量相比,2 mM DHA 增加了细胞存活率,并研究了这两种低 DHA 剂量之间的代谢差异。暴露于 1 mM DHA 显示出细胞燃料利用、线粒体 ROS 和糖酵解和线粒体能量的短暂变化,这些变化在暴露后 24 小时恢复正常。2 mM 剂量通过乙酰辅酶 A 诱导线粒体通量发生剧烈变化,并增加脂肪酸合酶的表达。与 1 mM 剂量不同,2 mM 暴露增加了线粒体 ROS 和 NAD(P)H 水平,并观察到 LDHA/LDHB 和乙酰辅酶 A 相关酶的持续变化。尽管细胞暴露于低细胞毒性(1 mM)和非细胞毒性(2 mM)的急性 DHA 剂量下,但线粒体代谢途径发生了显著变化。此外,2 mM DHA 急性剂量的增殖增加表明代谢适应发生,对存活和增殖有持续影响。随着电子烟气溶胶中 DHA 的外源性暴露增加,这项工作表明,急性或潜在慢性暴露引起的细胞代谢变化可能会影响细胞功能和存活。