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Structure and function of the human mitochondrial MRS2 channel
Open accessPreprint — published as 10.1038/s41594-024-01420-5
Abstract
The human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg 2+ transport across mitochondrial inner membranes, thus playing an important role in Mg 2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca 2+ -regulated, non-selective channel permeable to Mg 2+ , Ca 2+ , Na + and K + , which contrasts with its prokaryotic ortholog, CorA, operating as a Mg 2+ -gated Mg 2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, likely preventing the channel from collapsing the proton motive force that drives mitochondrial ATP synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- He, Z., Tu, Y.-C., Tsai, C.-W., Mount, J., Zhang, J., Tsai, M.-F., & Yuan, P.
- Affiliations
- Washington University in St. Louis (US)
- University of Virginia (US)
- Corresponding author
- Tsai, Ming-Feng
- Yuan, Peng
- Venue
- Nature Structural & Molecular Biology
- Publisher
- openRxiv
- Published
- 2023-08-15
- Volume
- 32
- Issue
- 3
- Pages
- 459-468
- ISSN
- 1545-9985 (ISSN-L)
- PMC
- PMC11922672
- OpenAlex
- W4404824429
- Cited by
- 17
- References
- 1
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 3 · 2023: 1
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Simons Foundation (SF 349247)
- National Institutes of Health
- Center for Cellular Imaging, Washington University
- National Institute of General Medical Sciences (R01GM144485, R01GM143440, R35GM151958)
- National Institute of Neurological Disorders and Stroke (R01NS109307, R01NS099341)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- MRS2, non-selective cation channels, calcium regulation, ion selectivity, Cora, inner mitochondrial membrane, cryo-EM structure
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