Specific Post-Translational Modifications of VDAC3 in ALS-SOD1 Model Cells Identified by High-Resolution Mass Spectrometry.

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Mitochondria are among the main producers of ROS, but they also suffer particularly from their harmful effects. Voltage-dependent anion-selective channels (VDACs) are the most represented proteins of the outer mitochondrial membrane where they form pores controlling the permeation of metabolites responsible for mitochondrial functions. For these reasons, VDACs contribute to mitochondrial quality control and the entire energy metabolism of the cell. In this work we assessed in an ALS cell model whether disease-related oxidative stress induces post-translational modifications (PTMs) in VDAC3, a member of the VDAC family of outer mitochondrial membrane channel proteins, known for its role in redox signaling. At this end, protein samples enriched in VDACs were prepared from mitochondria of an ALS model cell line, NSC34 expressing human SOD1G93A, and analyzed by nUHPLC/High-Resolution nESI-MS/MS. Specific over-oxidation, deamidation, succination events were found in VDAC3 from ALS-related NSC34-SOD1G93A but not in non-ALS cell lines. Additionally, we report evidence that some PTMs may affect VDAC3 functionality. In particular, deamidation of Asn215 alone alters single channel behavior in artificial membranes. Overall, our results suggest modifications of VDAC3 that can impact its protective role against ROS, which is particularly important in the ALS context. Data are available via ProteomeXchange with identifier PXD036728.", "claims": [{"id": "claim-method", "statement": "A freely available command-line script for Python 2.x (https://github.com/dblyon/deamidation), accessed on 1 December 2021 which uses the MaxQuant “evidence.txt” file, was used to estimate the percentage of deamidation in VDAC 3 for each cell line, as in [20].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36555496", "locator": "sections[17] \"Identification of Deamidation Sites on VDAC3\" paragraph 2", "quote": "A freely available command-line script for Python 2.x (https://github.com/dblyon/deamidation), accessed on 1 December 2021 which uses the MaxQuant “evidence.txt” file, was used to estimate the percentage of deamidation in VDAC 3 for each cell line, as in [20]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data are available via ProteomeXchange with identifier PXD036728.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36555496", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Data are available via ProteomeXchange with identifier PXD036728."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Specific over-oxidation, deamidation, succination events were found in VDAC3 from ALS-related NSC34-SOD1G93A but not in non-ALS cell lines.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:36555496", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Specific over-oxidation, deamidation, succination events were found in VDAC3 from ALS-related NSC34-SOD1G93A but not in non-ALS cell lines."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Specific over-oxidation, deamidation, succination events were found in VDAC3 from ALS-related NSC34-SOD1G93A but not in non-ALS cell lines.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:36555496"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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