As the most abundant divalent cation in the cell, magnesium ions (Mg²⁺) are involved in numerous enzymatic reactions and play a critical role in cellular metabolic pathways. The human mitochondrial Mg²⁺ channel, Mrs2, is essential for maintaining Mg²⁺ homeostasis in the mitochondrial matrix and regulating the production of ATP, the primary energy molecule. However, the three-dimensional structure of Mrs2 and the molecular mechanism underlying Mg²⁺ permeation have remained unclear.

On August 5, 2023, Yuequan Shen and Xue Yang's team from Nankai University published an article titled Molecular basis of Mg²⁺ permeation through the human mitochondrial Mrs2 channel in Nature Communications. In this study, cryo-EM was employed to resolve the structure of full-length Mrs2 molecules under four different conditions.

The structure revealed that hMrs2 adopts a five-fold symmetrical arrangement across different states, with the Mg²⁺ pore located at the center of the channel. Structural and functional studies showed that hMrs2 channels are permeable to Mg²⁺ in response to membrane potential, a conclusion that contradicts previous reports. Earlier studies suggested that changes in mitochondrial matrix Mg²⁺ concentrations induce conformational changes in the protein, thereby facilitating Mg²⁺ permeation.

Our findings indicate that the gating of the hMrs2 channel is mediated by a unique structural feature: five arginine residues (R332) form a ring with a Cl⁻ ion bound at its center. Molecular simulations revealed that Mg²⁺ hexahydrate attracts Cl⁻ binding, reducing Mg²⁺’s hydration number from six to four. This reduction allows Mg²⁺ to overcome the positively charged barrier formed by R332. With assistance from the negatively charged amino acid D329 in the mitochondrial matrix, Mg²⁺ tetrahydrate dissociates from Cl⁻, reverting to Mg²⁺ hexahydrate.

This mechanism of "cation transmembrane permeation" facilitated by negative ions is also observed in the permeation of Ca²⁺ through the extracellular calcium channel Orai. We anticipate that future research on ion channels will uncover more similar molecular mechanisms.