美国德州大学圣安东尼奥分校Muniswamy Madesh研究团队的一项最新研究表明，乳酸通过诱发内质网（ER）-线粒体Mg²⁺动态变化来整合细胞代谢。这一研究成果于2020年10月9日在线发表在国际学术期刊《细胞》上。

为了了解细胞内Mg²⁺（iMg²⁺）的时空动态如何整合到细胞信号传导中，研究人员进行了精密的筛选以揭示iMg²⁺的动态调节因子。研究发现乳酸是快速释放ER中存储Mg²⁺的激活因子，其促进了多种细胞类型中线粒体Mg²⁺（mMg²⁺）的吸收。

研究人员证明该过程具有温度敏感性，其由细胞内而不是细胞外信号介导。ER-线粒体Mg²⁺+动力学被L-乳酸选择性激活。此外，研究还发现Mrs2促进了乳酸介导的mMg²⁺的进入，而膜间隙环中的点突变限制了mMg²⁺的吸收。有趣的是，抑制mMg²⁺的吸收可减轻炎症引起的多器官衰竭。

总之，这些发现表明，乳酸有利于iMg²⁺的移动并将mMg²⁺的转运机制与主要的代谢反馈回路和线粒体能量产生联系起来。

研究人员表示，Mg²⁺是后生动物中最丰富的二价阳离子，是ATP、核酸和无数代谢酶的重要辅助因子。

附：英文原文

Title: Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism

Author: Cassidy C. Daw, Karthik Ramachandran, Benjamin T. Enslow, Soumya Maity, Brian Bursic, Matthew J. Novello, Cherubina S. Rubannelsonkumar, Ayah H. Mashal, Joel Ravichandran, Terry M. Bakewell, Weiwei Wang, Kang Li, Travis R. Madaris, Christopher E. Shannon, Luke Norton, Soundarya Kandala, Jeffrey Caplan, Subramanya Srikantan, Peter B. Stathopulos, W. Brian Reeves, Muniswamy Madesh

Issue&Volume: 2020-10-08

Abstract: Mg2+ is the most abundant divalent cation in metazoans and an essential cofactor for ATP,nucleic acids, and countless metabolic enzymes. To understand how the spatio-temporaldynamics of intracellular Mg2+ (iMg2+) are integrated into cellular signaling, we implemented a comprehensive screen todiscover regulators of iMg2+ dynamics. Lactate emerged as an activator of rapid release of Mg2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg2+ (mMg2+) uptake in multiple cell types. We demonstrate that this process is remarkably temperaturesensitive and mediated through intracellular but not extracellular signals. The ER-mitochondrialMg2+ dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediatedmMg2+ entry is facilitated by Mrs2, and point mutations in the intermembrane space looplimits mMg2+ uptake. Intriguingly, suppression of mMg2+ surge alleviates inflammation-induced multi-organ failure. Together, these findingsreveal that lactate mobilizes iMg2+ and links the mMg2+ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.

DOI: 10.1016/j.cell.2020.08.049

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31091-6