乳酸通過介導ER-線粒體Mg2+動態變化來整合細胞代謝

乳酸通過介導ER-線粒體Mg2+動態變化來整合細胞代謝

作者：

小柯機器人

發布時間：2020/10/11 21:15:21

美國德州大學聖安東尼奧分校Muniswamy Madesh研究團隊的一項最新研究表明，乳酸通過誘發內質網（ER）-線粒體Mg²⁺動態變化來整合細胞代謝。這一研究成果於2020年10月9日在線發表在國際學術期刊《細胞》上。

為了了解細胞內Mg²⁺（iMg²⁺）的時空動態如何整合到細胞信號傳導中，研究人員進行了精密的篩選以揭示iMg²⁺的動態調節因子。研究發現乳酸是快速釋放ER中存儲Mg²⁺的激活因子，其促進了多種細胞類型中線粒體Mg²⁺（mMg²⁺）的吸收。

研究人員證明該過程具有溫度敏感性，其由細胞內而不是細胞外信號介導。ER-線粒體Mg²⁺+動力學被L-乳酸選擇性激活。此外，研究還發現Mrs2促進了乳酸介導的mMg²⁺的進入，而膜間隙環中的點突變限制了mMg²⁺的吸收。有趣的是，抑制mMg²⁺的吸收可減輕炎症引起的多器官衰竭。

總之，這些發現表明，乳酸有利於iMg²⁺的移動並將mMg²⁺的轉運機制與主要的代謝反饋迴路和線粒體能量產生聯繫起來。

研究人員表示，Mg²⁺是後生動物中最豐富的二價陽離子，是ATP、核酸和無數代謝酶的重要輔助因子。

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

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