Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Department of Applied Genomics, Laboratory of Biomolecule Analysis, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan; Laboratory of Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
J Biol Chem. 2023 Feb;299(2):102837. doi: 10.1016/j.jbc.2022.102837. Epub 2022 Dec 26.
A high-salt diet significantly impacts various diseases, ilncluding cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmosensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of pyruvate dehydrogenase phosphorylation by direct osmosensing within mitochondria.
高盐饮食会显著影响多种疾病，包括癌症和免疫性疾病。最近的研究表明，体内高盐/高渗环境可能会改变疾病状态下癌症和免疫细胞的慢性特性。然而，人们对高渗应激下的急性代谢变化知之甚少。在这里，我们发现高渗应激几分钟后会诱导 HeLa 和 Raw264.7 细胞产生类似于瓦伯格的代谢重塑，并抑制脂肪酸氧化。关于类似于瓦伯格的重塑，我们确定在分离的线粒体中，丙酮酸脱氢酶磷酸化状态在高渗和低渗两种情况下都发生了双向变化（高渗时升高，低渗时降低），这表明线粒体本身具有急性渗透压感应机制。此外，我们证明类似于瓦伯格的重塑是 HeLa 细胞在高渗条件下维持 ATP 水平和存活所必需的。总之，我们的研究结果表明，细胞通过线粒体内部直接渗透压感应调节丙酮酸脱氢酶磷酸化来表现出渗透压应激下的急性代谢重塑。
