Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms

Area of Science:

• Cellular Physiology
• Mitochondrial Biology
• Ion Transport Mechanisms

Background:

• Magnesium ions (Mg²⁺) are crucial for cellular functions, including mitochondrial ATP synthesis and metabolism.
• The MRS2 channel in the inner mitochondrial membrane regulates Mg²⁺ influx and homeostasis, but its transport mechanisms remain unclear.
• MRS2 dysfunction impairs mitochondrial metabolism, highlighting its physiological importance.

Approach:

• Determined the cryo-electron microscopy (cryo-EM) structure of human MRS2 in the presence and absence of Mg²⁺ at high resolution (2.8 Å and 3.3 Å).
• Utilized mutagenesis and cellular divalent ion uptake assays to identify and validate key gating residues (R332 and M336).
• Investigated hydrogen bonding networks and identified two novel Mg²⁺-binding sites within the MRS2 soluble domain.

Key Points:

• The homo-pentameric structure of MRS2 revealed R332 and M336 as critical gating residues.
• A hydrogen bond network links the gating residue R332 to the soluble domain, suggesting a regulatory role.
• Two distinct Mg²⁺-binding sites were identified in the MRS2 soluble domain, differing from prokaryotic CorA.

Conclusions:

• This study provides the first detailed molecular structures of human MRS2, elucidating its gating and Mg²⁺ binding mechanisms.
• The findings offer a molecular framework for understanding Mg²⁺ translocation and regulation by MRS2.
• This research lays the groundwork for future studies on mitochondrial Mg²⁺ homeostasis and related disorders.