Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress
Abstract
:1. Introduction
2. Results
2.1. CRISPR/Cas9-Mediated MUT Gene Knockout in a HEK 293 Cell Line
2.2. Methylmalonic Acid and Propionylcarnitine Are Increased in MUT-KO Cells
2.3. MUT Knockout Does Not Affect Cell Viability and Proliferation
2.4. Label-Free Quantification for the Proteomic Analysis of MUT-KO versus WT
2.5. Bioinformatic Analysis: GO Terms Annotation
2.6. Rescuing MUT Protein Expression in a MUT-KO HEK 293 Cell Line
2.7. Validation of Proteomic Identifications in WT and MUT-KO and Protein Expression Levels Analysis in MUT-Rescue Cells
2.8. MUT Knockout Increases the Intracellular Levels of ROS
2.9. MUT Knockout Impairs Cell Viability and Mitochondrial Functionality in a Propionate-Enriched Culture Medium
2.10. MUT Knockout Hampers Cell Structure and Morphology Impacting on Proteoglycans and Glycoproteins
3. Discussion
3.1. MUT-KO and Cell Architecture Modification: Cytoskeleton, Cell Adhesion, and Cell Junction Organization
3.2. Metal Homeostasis Unbalances in MUT-KO
3.3. Mechanisms of Stress Linked to MUT: ROS, Hyperammonemia, and Propionate
3.4. Mitochondrial Alterations in MUT-KO
3.5. Intracellular Trafficking in MUT-KO
4. Material and Methods
4.1. Cell Cultures and Treatments
4.2. Genome Editing and Transfections
4.3. Methylmalonic Acid and Propionylcarnitine Measurement
4.4. Microscopy Analysis
4.5. ROS Assay
4.6. MTT and Neutral-Red Assays
4.7. Western Blot
4.8. Quantitative Real-Time PCR
4.9. Proteomics Sample Preparation
4.10. nanoLC-MS/MS Measurements
4.11. Data Processing Following LC-MS/MS Acquisition
4.12. Bioinformatic Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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GO Term | Downregulated | Upregulated |
---|---|---|
BP | Zinc II ion transmembrane transport (GO:0071577) | Intermediate filament bundle assembly (GO:0045110) |
BP | Positive regulation of cell communication (GO:0010647) | Coenzyme biosynthetic process (GO:0009108) |
MF | Divalent inorganic cation transmembrane transporter activity (GO:0072509) | Oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616) |
CC | Autophagosome (GO:0005776) | Mitochondrion (GO:0005739) |
CC | Autolysosome (GO:0044754) | Cytoskeleton (GO:0005856) |
UniProt Accession | Protein Name | Gene Name | Regulation | Log2 Difference |
---|---|---|---|---|
P22033 | Methylmalonyl-CoA mutase, mitochondrial | MUT | DOWN | −8.4 |
P23434 | Glycine cleavage system H protein, mitochondrial | GCSH | DOWN | −3.8 |
Q99595 | Mitochondrial import inner membrane translocase subunit Tim17-A | TIMM17A | DOWN | −3.3 |
Q8N4T8 | Carbonyl reductase family member 4 | CBR4 | DOWN | −3.1 |
Q9NUQ2 | 1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon | AGPAT5 | DOWN | −3.0 |
Q9Y375 | Complex I intermediate-associated protein 30, mitochondrial | NDUFAF1 | DOWN | −2.7 |
Q13772 | Nuclear receptor coactivator 4 | NCOA4 | DOWN | −1.1 |
P02794 | Ferritin heavy chain | FTH1 | DOWN | −0.9 |
P32119 | Peroxiredoxin-2 | PRDX2 | UP | 0.8 |
P27105 | Erythrocyte band 7 integral membrane protein | STOM | UP | 0.8 |
Q13057 | Bifunctional coenzyme A synthase | COASY | UP | 0.9 |
Q9H2U2 | Inorganic pyrophosphatase 2, mitochondrial | PPA2 | UP | 0.9 |
Q6YN16 | Hydroxysteroid dehydrogenase-like protein 2 | HSDL2 | UP | 1.0 |
Q16698 | 2,4-dienoyl-CoA reductase, mitochondrial | DECR1 | UP | 1.0 |
P35270 | Sepiapterin reductase | SPR | UP | 1.0 |
P23786 | Carnitine O-palmitoyltransferase 2, mitochondrial | CPT2 | UP | 1.0 |
Q8WVC6 | Dephospho-CoA kinase domain-containing protein | DCAKD | UP | 1.0 |
P35914 | Hydroxymethylglutaryl-CoA lyase, mitochondrial | HMGCL | UP | 1.0 |
P12532 | Creatine kinase U-type, mitochondrial | CKMT1A | UP | 1.1 |
Q9BRX8 | Redox-regulatory protein FAM213A | FAM213A | UP | 1.2 |
Q9NP58 | ATP-binding cassette sub-family B member 6, mitochondrial | ABCB6 | UP | 1.4 |
Q9NRG7 | Epimerase family protein SDR39U1 | SDR39U1 | UP | 1.4 |
Q9Y2Z9 | Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial | COQ6 | UP | 1.7 |
Q14790 | Caspase-8 | CASP8 | UP | 1.8 |
Q86UT6 | NLR family member X1 | NLRX1 | UP | 2.1 |
Q9BVL4 | Selenoprotein O | SELO | UP | 2.4 |
Q6PML9 | Zinc transporter 9 | SLC30A9 | UP | 2.4 |
O95139 | NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 | NDUFB6 | UP | 2.7 |
A8MXV4 | Nucleoside diphosphate-linked moiety X motif 19, mitochondrial | NUDT19 | UP | 3.6 |
Q8IYQ7 | Threonine synthase-like 1 | THNSL1 | UP | 3.7 |
Q9BSF4 | Uncharacterized protein C19orf52 | C19orf52 | UP | 4.0 |
Q9P0M9 | 39S ribosomal protein L27, mitochondrial | MRPL27 | UP | 4.5 |
P00395 | Cytochrome c oxidase subunit 1 | COX1 | UP | 5.7 |
UniProt Accession | Protein Name | Gene Name | Regulation | Log2 Difference | Cell Localization |
---|---|---|---|---|---|
Q93063 | Exostosin-2 | EXT2 | DOWN | −6.0 | ER, ERS, GA |
O00622 | Protein CYR61 | CYR61 | DOWN | −5.9 | ER, ERS |
Q9P2M7 | Cingulin | CGN | DOWN | −3.1 | CK, PM |
Q2PZI1 | Probable C-mannosyltransferase DPY19L1 Alpha-1,2-mannosyltransferase ALG9 Fibronectin Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA Annexin A3 Follistatin-related protein 1 | DPY19L1 | DOWN | −2.9 | N |
Q9H6U8 | ALG9 | DOWN | −2.8 | ER | |
P02751 | FN1 | DOWN | −2.7 | ER, ERS, PM | |
P33908 | MAN1A1 | DOWN | −2.7 | C, ER, ERS, GA | |
P12429 | ANXA3 | DOWN | −2.6 | C, ERS, PM | |
Q12841 | FSTL1 | DOWN | −2.5 | ER, ERS | |
Q12929 | Epidermal growth factor receptor kinase substrate 8 | EPS8 | DOWN | −2.1 | C, ERS, PM |
P08670 | Vimentin | VIM | DOWN | −2.0 | C, CK, ERS, N, P, PM |
P13591 | Neural cell adhesion molecule 1 | NCAM1 | DOWN | −1.6 | C, ERS, GA, PM |
P34741 | Syndecan-2 | SDC2 | DOWN | −0.9 | ER, ERS, GA, L, PM |
Q16706 | Alpha-mannosidase 2 | MAN2A1 | DOWN | −0.9 | ERS, GA |
P23352 | Anosmin-1 | KAL1 | DOWN | −0.8 | ERS, PM |
P10253 | Lysosomal alpha-glucosidase | GAA | UP | +0.8 | ERS, L, PM |
P12830 | Cadherin-1 | CDH1 | UP | +3.9 | CK, E, ERS, GA, PM |
Q6Y288 | Beta-1,3-glucosyltransferase | B3GALTL | UP | +5.8 | ER |
UniProt Accession | Protein Name | Gene Name | Regulation | Log2 Difference | Cell Localization |
---|---|---|---|---|---|
Q9ULF5 | Zinc transporter ZIP10 | SLC39A10 | DOWN | −4.5 | PM |
Q8IUH5 | Palmitoyltransferase ZDHHC17 | ZDHHC17 | DOWN | −4.2 | GA, PM |
Q13433 | Zinc transporter ZIP6 | SLC39A6 | DOWN | −2.6 | ER, PM |
Q9NY26 | Zinc transporter ZIP1 | SLC39A1 | DOWN | −1.1 | ER, PM |
Q13772 | Nuclear receptor coactivator 4 | NCOA4 | DOWN | −1.1 | L, N |
P02794 | Ferritin heavy chain | FTH1 | DOWN | −0.9 | C, ERS, L, N |
P48200 | Iron-responsive element-binding protein 2 | IREB2 | UP | +0.9 | C, M |
Q9NP58 | ATP-binding cassette sub-family B member 6, mitochondrial | ABCB6 | UP | +1.4 | C, E, ER, ERS, GA, M |
Q6PML9 | Zinc transporter 9 | SLC30A9 | UP | +2.4 | CK, ER, N |
UniProt Accession | Protein Name | Gene Name | Regulation | Log2 Difference | Cell Localization |
---|---|---|---|---|---|
P23434 | Glycine cleavage system H protein, mitochondrial | GCSH | DOWN | −3.8 | M |
P35914 | Hydroxymethylglutaryl-CoA lyase, mitochondrial | HMGCL | UP | +0.9 | C, M, P |
Q13057 | Bifunctional coenzyme A synthase | COASY | UP | +0.9 | ERS, M |
Q16698 | 2,4-dienoyl-CoA reductase, mitochondrial | DECR1 | UP | +1.0 | C, M, N |
P23786 | Carnitine O-palmitoyltransferase 2, mitochondrial | CPT2 | UP | +1.0 | M, N |
Q6P1M0 A8MXV4 | Long-chain fatty acid transport protein 4 Nucleoside diphosphate-linked moiety X motif 19, mitochondrial | SLC27A4 NUDT19 | UP UP | +1.1 +3.6 | ER, PM C, P |
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Costanzo, M.; Caterino, M.; Cevenini, A.; Jung, V.; Chhuon, C.; Lipecka, J.; Fedele, R.; Guerrera, I.C.; Ruoppolo, M. Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress. Int. J. Mol. Sci. 2020, 21, 4998. https://doi.org/10.3390/ijms21144998
Costanzo M, Caterino M, Cevenini A, Jung V, Chhuon C, Lipecka J, Fedele R, Guerrera IC, Ruoppolo M. Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress. International Journal of Molecular Sciences. 2020; 21(14):4998. https://doi.org/10.3390/ijms21144998
Chicago/Turabian StyleCostanzo, Michele, Marianna Caterino, Armando Cevenini, Vincent Jung, Cerina Chhuon, Joanna Lipecka, Roberta Fedele, Ida Chiara Guerrera, and Margherita Ruoppolo. 2020. "Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress" International Journal of Molecular Sciences 21, no. 14: 4998. https://doi.org/10.3390/ijms21144998