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Molecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel

Ming Li1, Yang Li1, Yue Lu1

  • 1State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300350, China.

Nature Communications
|August 5, 2023
PubMed

Insights

Mitochondrial RNA splicing 2 (Mrs2) channels magnesium (Mg2+) into mitochondria. New structures reveal an R-ring and chloride ion (Cl-) may control Mg2+ flow, driven by membrane potential.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biophysics

Background:

  • Mitochondrial RNA splicing 2 (Mrs2) is a crucial transporter of magnesium ions (Mg2+) across the inner mitochondrial membrane.
  • Mrs2's role in mitochondrial metabolism is significant, yet its precise Mg2+ permeation mechanism remains elusive.
  • Understanding Mrs2 function is vital for comprehending mitochondrial health and metabolic regulation.

Purpose of the Study:

  • To elucidate the structural basis and mechanism of Mg2+ transport by human Mrs2 (hMrs2).
  • To investigate the role of specific structural features and environmental factors in hMrs2 channel gating.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures of hMrs2.
  • Molecular dynamics (MD) simulations were performed to analyze channel dynamics and ion interactions.
  • Mitochondrial Mg2+ uptake assays were conducted to validate functional insights.

Main Results:

  • Four distinct cryo-EM structures revealed hMrs2 consistently forms symmetrical pentamers with conserved conformations.
  • A unique Cl--bound R-ring, formed by Arg332 residues, was identified as a key structural element.
  • MD simulations and uptake assays suggest the R-ring acts as a charge barrier, with Cl- potentially serving as a ferry, jointly regulating Mg2+ permeation.

Conclusions:

  • The study provides atomic-level insights into the assembly and Mg2+ permeation mechanism of hMrs2.
  • The R-ring and chloride ions are proposed to be critical components in gating Mg2+ flux.
  • Mitochondrial membrane potential is identified as the likely driving force for Mg2+ transport through hMrs2.

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