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

The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-mM), antagonistically regulate diver-gent metabolic pathways with several orders of magnitude affinity preference, but the physiological signifi-cance 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 accu-mulation 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, b-oxidation, thermogenesis, and HIF-1a-targets, in Mrs2-/- mice that are further enhanced under Western-diet -associ-ated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.

Automated summary

In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain and promotes metabolism, leading to decreased fat accumulation in the liver and browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. Lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.