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, ß-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.

The human MRS2 magnesium-binding domain is a regulatory feedback switch for channel activity.

Mitochondrial RNA splicing 2 (MRS2) forms a magnesium (Mg2+) entry protein channel in mitochondria. Whereas MRS2 contains two transmembrane domains constituting a pore on the inner mitochondrial membrane, most of the protein resides within the matrix. Yet, the precise structural and functional role of this obtrusive amino terminal domain (NTD) in human MRS2 is unknown. Here, we show that the MRS2 NTD self-associates into a homodimer, contrasting the pentameric assembly of CorA, an orthologous bacterial channel. Mg2+ and calcium suppress lower and higher order oligomerization of MRS2 NTD, whereas cobalt has no effect on the NTD but disassembles full-length MRS2. Mutating-pinpointed residues-mediating Mg2+ binding to the NTD not only selectively decreases Mg2+-binding affinity ∼sevenfold but also abrogates Mg2+ binding-induced secondary, tertiary, and quaternary structure changes. Disruption of NTD Mg2+ binding strikingly potentiates mitochondrial Mg2+ uptake in WT and Mrs2 knockout cells. Our work exposes a mechanism for human MRS2 autoregulation by negative feedback from the NTD and identifies a novel gain of function mutant with broad applicability to future Mg2+ signaling research.