Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethics Statement
2.2. Mutations in Patients
2.3. Patients
2.4. Cell Culture
2.5. Metabolite Extraction and Profiling by Targeted LC-MS
2.6. Proteomics Sample Preparation with Label-Free Quantification (LFQ)
2.7. LC-MS Instrument Settings for Shotgun Proteome Profiling and Data Analysis
2.8. Experimental Design, Statistical Rationale, Pathway, and Data Analyses
2.9. Simulations of Electron Transfer between the Iron–Sulfur Clusters of NDUFS1 and Prediction of Protein Stability of p.Phe124Leu in ND5
2.10. Measurement of Respiratory Chain Enzyme Activities
2.11. Live Cell Respiration Assay by Seahorse XFe96
2.12. Blue Native PAGE, Western Blot, and In-Gel Activity Assay of CI
2.13. Protein Sequence Alignment
3. Results
3.1. Substituted Amino Acids in ND5 and NDUFS1 are Highly Conserved from Bacteria to Human
3.2. Metabolome Profiling Revealed a Decrease of the GSH/GSSG Ratio in Both Patients
3.3. The TCA Cycle Metabolites—Fumaric and Malic Acid—Significantly Increased in Both Patients
3.4. Proteome Profiling
3.5. Gene Set Enrichment Analyses Reveal Glycolysis is Upregulated in the MT-ND5 Mutation and the Respiratory Chain is Down-Regulated in the NDUFS1 Mutations
3.6. The Rate of Electron Tunneling between the Iron–Sulfur Clusters N4 and N5 of NDUFS1 Was Predicted to Decrease Dramatically in a V228A Mutant
3.7. Decreased Stability of CI in Mutated NDUFS1 Prevents the Formation of Supercomplexes
3.8. Isolated CI Deficiency in Both Patients
3.9. Live Cell Respiration Assays Revealed a Low Oxygen Consumption Rate in Both Patients
4. Discussion
4.1. Specific Disassembly of the N-Module and the Entire Respirasome in Mutated NDUFS1
4.2. Disruption of The Electron Flow in Mutated NDUFS1
4.3. The Stalling of Proton Translocation in Mutated ND5 Is Assumed to Stop Electron Flow Without Any Consequences for Respirasome Formation
4.4. A Similar Pattern of Regulated Metabolites Was Identified in Both Patients, Mainly for ROS Defense and TCA Cycle Metabolites
4.5. CI Deficiency Leads to a Glycolytic Phenotype
4.6. Accumulation of Structural Proteins in Patients
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Activity Ratio Versus CS | CI | CI + III | CII | CII + III | CIII | CIV | F1Fo ATP Synthase |
---|---|---|---|---|---|---|---|
Patient MT-ND5 | 0.04 | 0.07 | 0.29 | 0.39 | 2.10 | 1.87 | 0.96 |
Patient NDUFS1 | 0.05 | 0.14 | 0.29 | 0.36 | 2.20 | 0.97 | 1.16 |
Reference range | 0.14–0.35 | 0.24–0.81 | 0.23–0.41 | 0.30–0.67 | 1.45–3.76 | 0.82–2.04 | 0.42–1.26 |
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Ni, Y.; Hagras, M.A.; Konstantopoulou, V.; Mayr, J.A.; Stuchebrukhov, A.A.; Meierhofer, D. Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer. Cells 2019, 8, 1149. https://doi.org/10.3390/cells8101149
Ni Y, Hagras MA, Konstantopoulou V, Mayr JA, Stuchebrukhov AA, Meierhofer D. Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer. Cells. 2019; 8(10):1149. https://doi.org/10.3390/cells8101149
Chicago/Turabian StyleNi, Yang, Muhammad A. Hagras, Vassiliki Konstantopoulou, Johannes A. Mayr, Alexei A. Stuchebrukhov, and David Meierhofer. 2019. "Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the Electron Transfer" Cells 8, no. 10: 1149. https://doi.org/10.3390/cells8101149