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

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.