Structure and function of the human mitochondrial MRS2 channel

  1. Zhihui He
  2. Yung-Chi Tu
  3. Chen-Wei Tsai
  4. Jonathan Mount
  5. Jingying Zhang
  6. Ming-Feng Tsai
  7. Peng Yuan

  • Curated by Biophysics Colab

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    Evaluation Statement (14 June 2024)

    The study by He et al. explores the structure and mechanisms of the human mitochondrial RNA splicing 2 (MRS2) protein, predicted to form Mg2+-selective channels in the mitochondrial inner membrane based on homology to the CorA family of prokaryotic Mg2+ channels. The authors use an innovative biochemical strategy to express MRS2 and perform single particle reconstructions in the absence and presence of key divalent cations. High resolution reconstructions of the pentameric channel reveal binding sites for Mg2+ and Ca2+, and electrophysiological investigations suggest that MRS2 is a Ca2+-regulated, cation-selective, Mg2+-permeable channel, in contrast to the Mg2+-regulated, Mg2+-selective CorA channel. This is an important study with interesting structural and functional observations, which will motivate further investigations of a potential role for MRS2 in mitochondrial Ca2+ signaling.

    Biophysics Colab recommends this study to scientists interested in the structure, function and regulation of cation channels as well as those working on mitochondrial transport.

    Biophysics Colab has evaluated this study as one that meets the following criteria:

    - Rigorous methodology

    - Transparent reporting

    - Appropriate interpretation

    (This evaluation refers to the version of record for this work, which is linked to and has been revised from the original preprint following peer review.)

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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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  1. Biophysics Colab

    Authors’ Response (6 May 2024)

    GENERAL ASSESSMENT

    He et al. explore the structure and mechanisms of human mitochondrial RNA splicing 2 protein (MRS2). MRS2 is a mitochondrial ion channel that was thought to form Mg2+-selective channels based on its homology to the CorA family of prokaryotic Mg2+ channels. Here, the authors used an innovative biochemical strategy to express MRS2 and perform single particle reconstructions of MRS2 in the absence and presence of key divalent cations. They obtained high resolution reconstructions of pentameric MRS2 and identified the divalent binding sites, some of which appear to be different from the prokaryotic counterparts. In addition, they showed that the structures of MRS2 appear to be more stable than CorA, exhibiting consistent features across different conditions, including in the presence of EDTA, Mg2+, and Ca2+. They further investigated electrophysiological characteristics of a mutant MRS2 channel and propose that it acts like a Ca2+-regulated, cation-selective, Mg2+-permeable channel, in contrast to the better characterized CorA channel, which is Mg2+-regulated and has a higher selectivity for Mg2+. This is an important study with interesting structural observations and an innovative hypothesis on function. We suggest that a more careful interpretation of the functional data and their relevance to MRS2 function in mitochondria would increase the overall value of the work.

    We would like to thank the colleagues from Biophysics Colab for reviewing our manuscript. We have revised our initial manuscript incorporating these recommendations and the reviewers’ comments from the publishing journal. We will also acknowledge Biophysics Colab in the published version of this work.

    RECOMMENDATIONS

    Essential revisions:

    1. Because R332 lines the channel pore, one would predict that neutralization of its positive charge would have an effect on ion permeation characteristics – either single channel conductance or relative permeabilities of different ions. Thus, it is unclear whether ion selectivity of the R332S mutation (probed in, for example, Fig. 4) is representative of WT MRS2. Ideally, selectivity would have been measured on the WT channel. If the authors performed similar experiments with R332D (if it expresses), would the observations be at least qualitatively similar?

    This is an excellent point. Indeed, it is possible that the R332S mutation affects the ion selectivity of MRS2. To test this, we have examined the ion permeation properties of the wild-type channel, MRS2WT. While MRS2WT conducted no detectable Mg2+ currents, its Na+ currents could be detected as shown in the original Figure 4a. MRS2WT still showed no anomalous mole fraction effect (AMFE), as the Na+ currents were unaffected by 100-µM Mg2+ (see new Extended Data Fig. 7a in the revised manuscript). Therefore, the lack of divalent cation selectivity of MRS2 was not artificially caused by the R332S background. We are in the process of mutating R332 to a wide range of other amino acids to better link the side-chain chemistry to MRS2 function. This will be an important future direction.

    Similarly, if the corresponding site in TmCorA (S) is mutated to R, would it behave like MRS2? Such data would increase confidence in the conclusions regarding selectivity. In addition, measuring relative permeabilities of ions would be significantly more informative than current magnitudes. If measurement of relative permeabilities is not feasible due to low current amplitudes, it would be important for the authors to tone down their conclusions on selectivity.

    Our results above have now demonstrated that R332 does not contribute to the ion selectivity of MRS2. Therefore, it is unlikely that mutating the corresponding residue of R332 in TmCorA (S284) to Arg would create profound effects on the ion selectivity of CorA. It should also be noted that the selectivity filter of CorA has been identified as the ‘GMN’ motif, which is far away from S284. However, we agree that S284R likely reduces the CorA conductance, and plan to test this mutant in future work.

    We are unable to measure the permeability ratio, as we have not established patch-clamp recordings of MRS2. This is certainly an important future direction. However, the lack of anomalous mole fraction effect (AMFE) indicates that MRS2 lacks the molecular property that confers divalent cation selectivity to CorA, and accordingly it is reasonable to conclude that MRS2 is a non-selective cation channel.

    A related technical consideration: from the description of the experiments, summarized in the bar graph in Fig. 4a (right), it’s not clear which/how many measurements were done on the same oocyte. It might be useful to mention that because oocyte-to-oocyte variability is a very important factor which can sometimes obfuscate observations and their interpretation. For all electrophysiological observations, it would be very useful to clarify whether the error bars are standard deviations (sd) or standard errors of the mean (sem). Because the replicates for the different measurements are highly variable – ranging between 6 and 34 – it might be more appropriate to compare sd instead of sem.

    Recordings from the same oocyte would only be counted as a single data point. We appreciate the reviewer's concern about using SD vs. SEM. However, we are comparing drastic differences. For example, we can detect Mg2+ currents with the R332S mutation but not with MRS2WT, and we can see AMFE in CorA but not in MRS2. These major effects are unlikely affected by whether we present the data with SEM or SD.

    1. Recordings to examine currents at more hyperpolarizing potentials are essential for drawing conclusions about the function of MRS2 in mitochondria. The voltage at which the oocytes are clamped in all electrophysiological measurements (-60 mV) might be very different from the voltage at which MRS2 operates in a native environment. If MRS2 is susceptible to voltage-dependent block by the permeant divalents (Ca2+/Mg2+), their presence could influence currents observed at hyperpolarized potentials.

    We have now recorded MRS2WT at -120 mV. No Mg2+ currents or AMFE were observed, as in our recordings at -60 mV.

    1. P4, “In the divalent-free MRS2EDTA structure, discernible ion densities are absent in the central pore.” Because the map was generated by imposing C5 symmetry during processing (with the pore located at the central symmetry axis) and the buffer contained NaCl (which is known to permeate MRS2), we would expect the maps to show some density for ions in addition to noise generated during data processing. Although these maps were not available for this review, inspection of related maps for MRS2 (EMDB-41628 and EMDB-35631) indeed show density within the pore in the presence of NaCl and EDTA. Also, the symmetrical diamond-shaped density (either from ions or noise) shown in Extended Data Fig. 5 has the characteristics of being enhanced during processing with imposed C5 symmetry. It would be important for the authors to clarify how they drew conclusions about the absence or presence of ion densities along the pore in the different maps they refined. Showing density at equivalent positions within the pore for their different structures would be a nice addition to Ext. Data Fig. 5.

    This is an excellent point. Assignment of ions in cryo-EM density maps is indeed challenging because of noise, especially at the symmetry axis. We have carefully examined these densities and the chemical environment nearby to assign these ions. We have now included density maps at these equivalent positions in the revised manuscript.

    1. The currents shown in recordings from oocytes were at negative voltages and were elicited by replacement of NMDG with smaller monovalent or divalent cations. For these currents to be rigorously attributed to MSR2, it would have been important to perform the experiments in parallel with control oocytes not expressing the protein (either injected with water or uninjected). However, we appreciate that this would require considerable effort to address in retrospect. One solution would be for the authors to identify a few key conditions, perhaps those shown in Fig. 3, and repeat them with appropriate controls to allow comparison of the data in a bar chart or related graph. The data shown in Fig. 4a for the WT protein could be considered a reasonable control in such experiments, so perhaps the authors could point this out to the reader?

    In the new Extended Data Fig. 7a in the revised manuscript, we provided data showing that uninjected oocytes, or oocytes expressing the mitochondrial calcium uniporter, showed no Mg2+ currents, suggesting that the observed Mg2+ currents were mediated by MRS2. Additionally, we could inhibit these currents with cobalt hexammine (Fig. 3c-d), or drastically reduce the currents with MRS2 mutations (Fig. 5a-b). These observations all support the conclusion that we are observing MRS2 currents.

    Optional suggestions:

    1. In several of the 2D class averages, particularly in Extended Fig. 1a, MRS2 seems to be located off-center, almost at the edge of the micelle. With a relatively small transmembrane core, it is possible that MRS2 is “freely diffusing” in the micelle, in which the lateral pressure that the transmembrane domains are subject to is quite different from the scenario where the protein is more at the micelle center. Would this observation have any bearing on the function/reconstruction of MRS2, particularly given that limited structural changes are observed in the transmembrane segments between divalent free and with-divalent conditions? The 2D classes are likely from an early stage of reconstruction. It might be worthwhile to show 2D classes of the final set of particles used for the reconstruction.

    This is an interesting point. It may influence the conformations of channels that are very sensitive to their surrounding environments. For MRS2, we do not think that the off-center location in detergent micelles significantly changes its structure. We have later also determined the cryo-EM structure of MRS2 in lipid nanodiscs, which is identical to the structure in detergents.

    1. It is interesting that, in the reconstructions with Ca2+, the peripheral domains become more heterogenous than in Mg2+ or EDTA (Extended Fig. 1). How does this region of the map compare with the location of divalent site 3?

    The divalent site 3 is not located within the peripheral domains. The cryo-EM densities, as shown in Extended Data Fig. 5, are well defined near site 3 in both Ca2+ and Mg2+ conditions.

    1. Would Ca2+ (but not Mg2+) binding make this region more dynamic and could that have any mechanistic significance?

    This is a very interesting point. We did not see apparent structural changes in Ca2+ vs Mg2+ conditions and hypothesize that Ca2+ regulation may arise from differences in structural dynamics. We have been using other biophysical techniques such as high-speed atomic force microscopy to investigate these differences.

    1. Does the Ca2+ reconstruction (Extended Fig. 1) have a preferred orientation? The elevation/azimuth plots show an asymmetry (along the elevation) which might have appeared from some kind of bias. It is not clear if the authors have tried to address this, say by rebalancing 2D classes. 3D FSC curves might help test/address this bias.

    In general, particles in Ca2+ conditions are more prone to aggregation and appear to have some degrees of preferred orientation.

    1. While the structural difference between MRS2 and TmCorA at the level of the a/b _domain is clear in Extended Fig. 3, it may be worthwhile to compare them in the context of the pentamer. Particularly, does the difference alter the interfaces? Are the surface electrostatic properties of the domain similar? Considering that these domains mediate divalent regulation, comparison of these properties might help readers better appreciate similarities/differences in their structural attributes.

    These are very good points to add to structural comparison between MRS2 and TmCorA.

    1. With respect to Fig. 1D, do the authors observe any side portals for ion entry/exit into the pore? The soluble domains of MRS2 seems to form a highly electronegative cavity for ion translocation. Are there any single channel conductance measurements of MRS2 that would argue for the importance of these electronegative surfaces?

    No apparent side portals for ion entry were observed. We have not done single-channel recordings yet. Since CorA single-channel recordings have not been reported to date, we speculate that MRS2/CorA might be too slow to produce detectable single-channel currents.

    1. It doesn’t appear that any approximations of the relative affinity of MRS2 for Mg2+/Ca2+ (e.g. EC50 measurements) are available at this point. It might therefore have been better for the Mg2+ reconstructions to include EGTA in the buffers to sequester Ca2+, given that conventional filter papers used during plunge-freezing are fabricated with ash containing a lot of Ca2+/Zn2+. This would have helped to at least partially address questions about whether the observed divalent densities truly correspond to the ions used during cryoEM sample preparation.If the authors are not able to do Mg2+ reconstructions with EGTA in the buffer, it would be of benefit to at least comment on this issue in the discussion of the results.

    This is a very good control experiment to validate Mg2+ binding. Given that the MRS2 structure in 10 mM EDTA (without added divalent ions) is essentially the same as that in high Mg2+ or Ca2+, we would expect that MRS2 structures in Mg2+ & EGTA conditions are likely the same as in other conditions.

    1. What is the orientation of MRS2 when it is in the plasma membrane? If the orientation is such that the regulatory domains face the cytosol, inside-out patches would be more informative, appropriate and reliable for addressing the mechanistic questions that the authors are exploring. The authors should comment on whether or not the orientation is known.

    The MRS2 orientation is oocyte membranes is currently unknown. It will be interesting to determine the orientation in the future.

    1. P4, “additional unique Mg2+ binding site (site3)”. In Fig. 2, it would be beneficial to label and specify the distances between the binding residues and the ions, along with elucidating the nature of the interactions they form.

    This is a good point. However, we do not want to overinterpret the structure to specify how the ion is coordinated by side-chain atoms because of the limited resolution.

    10. P9, in the discussion about structural dynamics. Drawing conclusions about the rigidity of MRS2's structure may be premature at this stage. Since the MRS2 structures are pentameric, the unique feature of asymmetrical particles can potentially be averaged by the features of symmetrical particles, particularly when a substantial number of symmetrical particles are present. This can pose a challenge in isolating and distinguishing asymmetrical structure from the overall dataset, even when applying C1 symmetry during the data processing. It would be helpful to employ techniques such as 3D Variability Analysis from CryoSPARC or subtracting the density of a monomer for focused 3D classification that might provide more insights into the structural dynamics of MRS2.

    To better investigate the structural dynamics of MRS2, we plan to apply more appropriate biophysical methods such as high-speed atomic force microscopy.

    (This is a response to peer review conducted by Biophysics Colab on version 1 of this preprint.)

  2. Biophysics Colab

    Evaluation Statement (14 June 2024)

    The study by He et al. explores the structure and mechanisms of the human mitochondrial RNA splicing 2 (MRS2) protein, predicted to form Mg2+-selective channels in the mitochondrial inner membrane based on homology to the CorA family of prokaryotic Mg2+ channels. The authors use an innovative biochemical strategy to express MRS2 and perform single particle reconstructions in the absence and presence of key divalent cations. High resolution reconstructions of the pentameric channel reveal binding sites for Mg2+ and Ca2+, and electrophysiological investigations suggest that MRS2 is a Ca2+-regulated, cation-selective, Mg2+-permeable channel, in contrast to the Mg2+-regulated, Mg2+-selective CorA channel. This is an important study with interesting structural and functional observations, which will motivate further investigations of a potential role for MRS2 in mitochondrial Ca2+ signaling.

    Biophysics Colab recommends this study to scientists interested in the structure, function and regulation of cation channels as well as those working on mitochondrial transport.

    Biophysics Colab has evaluated this study as one that meets the following criteria:

    - Rigorous methodology

    - Transparent reporting

    - Appropriate interpretation

    (This evaluation refers to the version of record for this work, which is linked to and has been revised from the original preprint following peer review.)

  3. Biophysics Colab

    Consolidated peer review report (2 November 2023)

    GENERAL ASSESSMENT

    He et al. explore the structure and mechanisms of human mitochondrial RNA splicing 2 protein (MRS2). MRS2 is a mitochondrial ion channel that was thought to form Mg2+-selective channels based on its homology to the CorA family of prokaryotic Mg2+ channels. Here, the authors used an innovative biochemical strategy to express MRS2 and perform single particle reconstructions of MRS2 in the absence and presence of key divalent cations. They obtained high resolution reconstructions of pentameric MRS2 and identified the divalent binding sites, some of which appear to be different from the prokaryotic counterparts. In addition, they showed that the structures of MRS2 appear to be more stable than CorA, exhibiting consistent features across different conditions, including in the presence of EDTA, Mg2+, and Ca2+. They further investigated electrophysiological characteristics of a mutant MRS2 channel and propose that it acts like a Ca2+-regulated, cation-selective, Mg2+-permeable channel, in contrast to the better characterized CorA channel, which is Mg2+-regulated and has a higher selectivity for Mg2+. This is an important study with interesting structural observations and an innovative hypothesis on function. We suggest that a more careful interpretation of the functional data and their relevance to MRS2 function in mitochondria would increase the overall value of the work.

    RECOMMENDATIONS

    Essential revisions:

    1. Because R332 lines the channel pore, one would predict that neutralization of its positive charge would have an effect on ion permeation characteristics – either single channel conductance or relative permeabilities of different ions. Thus, it is unclear whether ion selectivity of the R332S mutation (probed in, for example, Fig. 4) is representative of WT MRS2. Ideally, selectivity would have been measured on the WT channel. If the authors performed similar experiments with R332D (if it expresses), would the observations be at least qualitatively similar? Similarly, if the corresponding site in TmCorA (S) is mutated to R, would it behave like MRS2? Such data would increase confidence in the conclusions regarding selectivity. In addition, measuring relative permeabilities of ions would be significantly more informative than current magnitudes. If measurement of relative permeabilities is not feasible due to low current amplitudes, it would be important for the authors to tone down their conclusions on selectivity. A related technical consideration: from the description of the experiments, summarized in the bar graph in Fig. 4a (right), it’s not clear which/how many measurements were done on the same oocyte. It might be useful to mention that because oocyte-to-oocyte variability is a very important factor which can sometimes obfuscate observations and their interpretation. For all electrophysiological observations, it would be very useful to clarify whether the error bars are standard deviations (sd) or standard errors of the mean (sem). Because the replicates for the different measurements are highly variable – ranging between 6 and 34 – it might be more appropriate to compare sd instead of sem.

    2. Recordings to examine currents at more hyperpolarizing potentials are essential for drawing conclusions about the function of MRS2 in mitochondria. The voltage at which the oocytes are clamped in all electrophysiological measurements (-60 mV) might be very different from the voltage at which MRS2 operates in a native environment. If MRS2 is susceptible to voltage-dependent block by the permeant divalents (Ca2+/Mg2+), their presence could influence currents observed at hyperpolarized potentials.

    3. P4, “In the divalent-free MRS2EDTA structure, discernible ion densities are absent in the central pore.” Because the map was generated by imposing C5 symmetry during processing (with the pore located at the central symmetry axis) and the buffer contained NaCl (which is known to permeate MRS2), we would expect the maps to show some density for ions in addition to noise generated during data processing. Although these maps were not available for this review, inspection of related maps for MRS2 (EMDB-41628 and EMDB-35631) indeed show density within the pore in the presence of NaCl and EDTA. Also, the symmetrical diamond-shaped density (either from ions or noise) shown in Extended Data Fig. 5 has the characteristics of being enhanced during processing with imposed C5 symmetry. It would be important for the authors to clarify how they drew conclusions about the absence or presence of ion densities along the pore in the different maps they refined. Showing density at equivalent positions within the pore for their different structures would be a nice addition to Ext. Data Fig. 5.

    4. The currents shown in recordings from oocytes were at negative voltages and were elicited by replacement of NMDG with smaller monovalent or divalent cations. For these currents to be rigorously attributed to MSR2, it would have been important to perform the experiments in parallel with control oocytes not expressing the protein (either injected with water or uninjected). However, we appreciate that this would require considerable effort to address in retrospect. One solution would be for the authors to identify a few key conditions, perhaps those shown in Fig. 3, and repeat them with appropriate controls to allow comparison of the data in a bar chart or related graph. The data shown in Fig. 4a for the WT protein could be considered a reasonable control in such experiments, so perhaps the authors could point this out to the reader?

    Optional suggestions:

    1. In several of the 2D class averages, particularly in Extended Fig. 1a, MRS2 seems to be located off-center, almost at the edge of the micelle. With a relatively small transmembrane core, it is possible that MRS2 is “freely diffusing” in the micelle, in which the lateral pressure that the transmembrane domains are subject to is quite different from the scenario where the protein is more at the micelle center. Would this observation have any bearing on the function/reconstruction of MRS2, particularly given that limited structural changes are observed in the transmembrane segments between divalent free and with-divalent conditions? The 2D classes are likely from an early stage of reconstruction. It might be worthwhile to show 2D classes of the final set of particles used for the reconstruction.

    2. It is interesting that, in the reconstructions with Ca2+, the peripheral domains become more heterogenous than in Mg2+ or EDTA (Extended Fig. 1). How does this region of the map compare with the location of divalent site 3?

    3. Would Ca2+ (but not Mg2+) binding make this region more dynamic and could that have any mechanistic significance?

    4. Does the Ca2+ reconstruction (Extended Fig. 1) have a preferred orientation? The elevation/azimuth plots show an asymmetry (along the elevation) which might have appeared from some kind of bias. It is not clear if the authors have tried to address this, say by rebalancing 2D classes. 3D FSC curves might help test/address this bias.

    5. While the structural difference between MRS2 and TmCorA at the level of the a/b domain is clear in Extended Fig. 3, it may be worthwhile to compare them in the context of the pentamer. Particularly, does the difference alter the interfaces? Are the surface electrostatic properties of the domain similar? Considering that these domains mediate divalent regulation, comparison of these properties might help readers better appreciate similarities/differences in their structural attributes.

    6. With respect to Fig. 1D, do the authors observe any side portals for ion entry/exit into the pore? The soluble domains of MRS2 seems to form a highly electronegative cavity for ion translocation. Are there any single channel conductance measurements of MRS2 that would argue for the importance of these electronegative surfaces?

    7. It doesn’t appear that any approximations of the relative affinity of MRS2 for Mg2+/Ca2+ (e.g. EC50 measurements) are available at this point. It might therefore have been better for the Mg2+ reconstructions to include EGTA in the buffers to sequester Ca2+, given that conventional filter papers used during plunge-freezing are fabricated with ash containing a lot of Ca2+/Zn2+. This would have helped to at least partially address questions about whether the observed divalent densities truly correspond to the ions used during cryoEM sample preparation.If the authors are not able to do Mg2+ reconstructions with EGTA in the buffer, it would be of benefit to at least comment on this issue in the discussion of the results.

    8. What is the orientation of MRS2 when it is in the plasma membrane? If the orientation is such that the regulatory domains face the cytosol, inside-out patches would be more informative, appropriate and reliable for addressing the mechanistic questions that the authors are exploring. The authors should comment on whether or not the orientation is known.

    9. P4, “additional unique Mg2+ binding site (site3)”. In Fig. 2, it would be beneficial to label and specify the distances between the binding residues and the ions, along with elucidating the nature of the interactions they form.

    10. P9, in the discussion about structural dynamics. Drawing conclusions about the rigidity of MRS2's structure may be premature at this stage. Since the MRS2 structures are pentameric, the unique feature of asymmetrical particles can potentially be averaged by the features of symmetrical particles, particularly when a substantial number of symmetrical particles are present. This can pose a challenge in isolating and distinguishing asymmetrical structure from the overall dataset, even when applying C1 symmetry during the data processing. It would be helpful to employ techniques such as 3D Variability Analysis from CryoSPARC or subtracting the density of a monomer for focused 3D classification that might provide more insights into the structural dynamics of MRS2.

    REVIEWING TEAM

    Reviewed by:

    Sandipan Chowdhury, Assistant Professor, University of Iowa: single-particle EM, electrophysiology, membrane transport biophysics

    Nanami Senoo, Postdoctoral Fellow, Johns Hopkins University: mitochondrial transport

    Xiaofeng Tan, Research Fellow, NINDS, NIH, USA: structural biology, cryo-EM, ion channel structure and mechanisms

    Curated by:

    Merritt Maduke, Associate Professor, Stanford University School of Medicine, USA

  4. Version published to 10.1101/2023.08.12.553106v1 on bioRxiv