NMR Structural and Biophysical Analysis of the Disease-Linked Inner Mitochondrial Membrane Protein MPV17

Sperl, Laura E.; Hagn, Franz

doi:10.1016/j.jmb.2021.167098

Cited by 9 publications

(18 citation statements)

References 41 publications

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“…In addition, modeling the interaction of MPV17 with MIC60 and CypD leads to propose a putative orientation of the protein, while the crystallographic structure and topology of the protein is extremely difficult to obtain and where only limited biophysical studies have been conducted for MPV17 structure unraveling (Sperl & Hagn, 2021). Indeed, based on the MPV17 partners validated by immunoprecipitation, we suggest that the N-terminal domain is located in the intermembrane space (IMS) and the C-terminal domain in the matrix, with the five transmembrane domains spanning the inner mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 99%

“…However, another study revealed that MPV17 acts as a channel modulating the selective entry of metabolites such as uridine or orotate, and is sensitive to oxidative stress (Corra et al, 2023;Mukherjee et al, 2023;Sperl & Hagn, 2021). Upon oxidative stress, the protein could oligomerize, promoting the selective entry of metabolites for mtDNA repair or replication (Sperl & Hagn, 2021). SYM1, the yeast ortholog of MPV17, exhibits strong evolutionary conservation as its depletion can be complemented by human MPV17 expression which can rescue the impaired OXPHOS activity and growth defect under non-fermentable condition (Dallabona et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function

Meurant,

Amato,

Mauclet

et al. 2024

Preprint

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Mitochondrial DNA depletion syndromes are severe genetic disorders associated with mutations in a variety of genes including MPV17, encoding a protein of the inner mitochondrial membrane with an unclear function. In this study, using BioID technology, we identified MPV17 interacting partners among which proteins from the MICOS complex. However, MPV17 knockout did not impact mitochondrial ultrastructure, but led to increased mitochondria-derived vesicles formation and altered mitochondrial permeability transition pore. Furthermore, MPV17 KO cells exhibited higher mitochondrial calcium levels and reactive oxygen species, leading to mtDNA degradation, a phenomenon prevented by blocking mitochondrial calcium entry or treating cells with antioxidant. We thus propose a function for MPV17 as a potential additional member of the mitochondrial permeability transition pore, whereas in the absence of the protein, the build-up of calcium inside the mitochondria would lead to mtDNA degradation caused by increased oxidative damages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function

Meurant,

Amato,

Mauclet

et al. 2024

Preprint

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“…Electrophysiological studies showed that MPV17 is a nonselective channel with gating regulated by different factors including membrane potential, redox state, and protein phosphorylation [80]. Using nuclear magnetic resonance (NMR), it was shown that MPV17 protein has six membraneembedded α-helices [81]. Under oxidative stress, it forms disulfide-stabilized oligomeric pores and these may serve to transport DNA precursors into the mitochondrial matrix to compensate for damage caused by oxidative stress.…”

Section: Role Of Mitochondrial Membrane Transporters In Mtdna Mainten...mentioning

confidence: 99%

“…Under oxidative stress, it forms disulfide-stabilized oligomeric pores and these may serve to transport DNA precursors into the mitochondrial matrix to compensate for damage caused by oxidative stress. Pathogenic variants in MPV17 prevent these oligomerization properties [81].…”

Section: Role Of Mitochondrial Membrane Transporters In Mtdna Mainten...mentioning

confidence: 99%

Mitochondrial Membranes and Mitochondrial Genome: Interactions and Clinical Syndromes

Almannai¹,

Salah

El‐Hattab

2022

Membranes

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Mitochondria are surrounded by two membranes; the outer mitochondrial membrane and the inner mitochondrial membrane. They are unique organelles since they have their own DNA, the mitochondrial DNA (mtDNA), which is replicated continuously. Mitochondrial membranes have direct interaction with mtDNA and are therefore involved in organization of the mitochondrial genome. They also play essential roles in mitochondrial dynamics and the supply of nucleotides for mtDNA synthesis. In this review, we will discuss how the mitochondrial membranes interact with mtDNA and how this interaction is essential for mtDNA maintenance. We will review different mtDNA maintenance disorders that result from defects in this crucial interaction. Finally, we will review therapeutic approaches relevant to defects in mitochondrial membranes.

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“…Finally, the oligomeric state of the MP in the nanodisc preparation needs to be monitored in order to optimize the assembly conditions to obtain a sample with a homogeneous oligomeric state. This can be done by multi-angle light scattering (MALS) and mass spectrometric or chemical cross-linking protocols. − More recently, fusion protein strategies were used to determine the number of MPs in nanodiscs, ranging from larger integral MPs to single TMHs. − …”

Section: Lipid Nanodiscsa Lipid-based and Native-like Membrane Mimeticmentioning

confidence: 99%

Lipid Nanodiscs for High-Resolution NMR Studies of Membrane Proteins

Günsel

Hagn

2021

Chem. Rev.

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Membrane proteins (MPs) play essential roles in numerous cellular processes. Because around 70% of the currently marketed drugs target MPs, a detailed understanding of their structure, binding properties, and functional dynamics in a physiologically relevant environment is crucial for a more detailed understanding of this important protein class. We here summarize the benefits of using lipid nanodiscs for NMR structural investigations and provide a detailed overview of the currently used lipid nanodisc systems as well as their applications in solution-state NMR. Despite the increasing use of other structural methods for the structure determination of MPs in lipid nanodiscs, solution NMR turns out to be a versatile tool to probe a wide range of MP features, ranging from the structure determination of small to medium-sized MPs to probing ligand and partner protein binding as well as functionally relevant dynamical signatures in a lipid nanodisc setting. We will expand on these topics by discussing recent NMR studies with lipid nanodiscs and work out a key workflow for optimizing the nanodisc incorporation of an MP for subsequent NMR investigations. With this, we hope to provide a comprehensive background to enable an informed assessment of the applicability of lipid nanodiscs for NMR studies of a particular MP of interest.

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NMR Structural and Biophysical Analysis of the Disease-Linked Inner Mitochondrial Membrane Protein MPV17

Cited by 9 publications

References 41 publications

In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function

In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function

Mitochondrial Membranes and Mitochondrial Genome: Interactions and Clinical Syndromes

Lipid Nanodiscs for High-Resolution NMR Studies of Membrane Proteins

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