Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress

Cell Rep. 2023 Mar 28;42(3):112155. doi: 10.1016/j.celrep.2023.112155. Epub 2023 Feb 27.


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 the physiological significance of this competition remains elusive. 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 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, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2-/- mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.

Keywords: CP: Metabolism; HCC; HIF1; MCU; Mrs2; NAFLD; Western diet; adipose expansion; adipose tissue; calcium channel; cardiometabolic disease; diabetes; energy imbalance; hepatocytes; liver; magnesium channel; metabolic disease; metabolic syndrome; mitochondrial dysfunction; obesity; whole-body metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue, Brown* / metabolism
  • Adipose Tissue, White / metabolism
  • Animals
  • Cation Transport Proteins
  • Diet
  • Diet, High-Fat
  • Energy Metabolism* / genetics
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins
  • Obesity / metabolism
  • Thermogenesis / genetics


  • Cation Transport Proteins
  • Mitochondrial Proteins
  • Mrs2 protein, mouse