Limiting Mrs2-Dependent Mg2+ Uptake Induces Metabolic Programming in Prolonged Dietary Stress

MANUSCRIPT ABSTRACT: The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-µM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but its physiological significance of this competition remains largely unknown. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency further restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, b-oxidation, thermogenesis, and HIF-1a-targets, in Mrs2-/- mice that are further enhanced under Western diet-associated metabolic stress. Thus, lowering mMg2+ is sufficient to promote metabolism and dampens diet induced obesity and metabolic syndrome. Investigate the role of mitochondrial magnesium in regulating metabolism and mitochondrial function. WT and Mrs2 KO mice were utilized to examine this, and an obesogenic diet called Western Diet (control diet called chow diet). Gene expression studies were conducted on the liver and iWAT tissues as described to examine the metabolic reprogramming induced by the chronic Western diet. N=3 biological replicates (mice) per group.手稿摘要：细胞内丰度最高的二价阳离子——镁离子（Mg²+，浓度范围为毫摩尔级，mM）与钙离子（Ca²+，浓度范围为纳摩尔-微摩尔级，nM-µM）可通过跨数量级的亲和力偏好，拮抗调控多条迥异的代谢通路，但二者间的这种竞争效应的生理学意义迄今尚未得到充分阐明。在喂食西式饮食（Western Diet）的小鼠模型中，线粒体镁离子通道Mrs2（mitochondrial Mg²+ channel Mrs2）的基因敲除可阻断体重增长、增强线粒体活性、减少肝脏脂肪蓄积，并显著诱导白色脂肪组织褐变。Mrs2缺失还会抑制柠檬酸从线粒体的向外转运，使其无法支撑从头脂肪生成过程。由于柠檬酸是内源性镁离子螯合剂，这一现象或代表机体感知镁离子缺乏时启动的适应性应答。对肝脏与白色脂肪组织的转录谱分析显示，在Mrs2基因敲除（Mrs2-/-）小鼠中，参与糖酵解、β-氧化、产热过程以及缺氧诱导因子-1α（HIF-1α）靶基因调控的相关基因表达水平更高；且在西式饮食相关的代谢应激条件下，该表达上调效应会进一步增强。综上，降低线粒体镁离子水平足以促进机体代谢，并缓解饮食诱导的肥胖与代谢综合征。本研究旨在探究线粒体镁离子在调控代谢与线粒体功能中的作用。实验采用野生型（wild type, WT）与Mrs2基因敲除（knockout, KO）小鼠，使用致肥胖的西式饮食（Western Diet）作为造模饮食，对照饮食为普通饲料饮食（chow diet）。按照既定方案对肝脏与腹股沟白色脂肪组织（inguinal white adipose tissue, iWAT）开展基因表达分析，以考察慢性西式饮食诱导的代谢重编程效应。每组设置3只生物学重复小鼠。