MRS2 missense variation at Asp216 abrogates inhibitory Mg binding, potentiating cell migration and apoptosis resistance.

Mitochondrial magnesium (Mg) is a crucial modulator of protein stability, enzymatic activity, ATP synthesis, and cell death. Mitochondrial RNA splicing protein 2 (MRS2) is the main Mg channel in the inner mitochondrial membrane that mediates influx into the matrix. Recent cryo-electron microscopy (cryo-EM) human MRS2 structures exhibit minimal conformational changes at high and low Mg, yet the regulation of human MRS2 and orthologues by Mg binding to analogous matrix domains has been well established.

Limiting Mrs2-dependent mitochondrial Mg uptake induces metabolic programming in prolonged dietary stress.

The most abundant cellular divalent cations, Mg (mM) and Ca (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 Mg 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.

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

Mitochondrial RNA splicing 2 (MRS2) forms a magnesium (Mg) 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.