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Yang Ni, Muhammad Hagras, Vassiliki Konstantopoulou, Johannes Mayr, Alexei Stuchebrukhov, David Meierhofer (Max Planck Institute for Molecular Genetics, Berlin; Freie Universität Berlin, Berlin, Germany; UC Davis, USA; Medical Univeristy of Vienna, Austria; Paracelsus Medical University, Salzburg, Austria)
Functional difficiencies in complex I (CI), the first enzyme of the mitochondrial oxidative phosphorylation system, lead to inborn errors of metabolism. To dissect the pathological mechanisms of CI deficiency, we used skin fibroblast cells from two patients carrying missense mutations in core subunits of CI, and we applied proteome- and metabolome profiling. Proteome profiling showed that the N-module of CI was dramastically downregulated in the NDUFS1 patient, indicating the instability of CI assembly and its dissociation. Compared with controls, Blue Native PAGE illustrated a less amount of respiratory chain supercomplexes in the NDUFS1 patient. In the MT-ND5 patient, gene set enrichment analysis revealed that the glycolysis pathway was significantly upregulated (p-value ≤ 0.0001), which was validated by live-cell microrespirometry. Proteome profiling revealed that the molecular consequences of NDUFS1 and MT-ND5 mutations were different on the protein level. In contrast, metabolome profiling illustrated that the pattern of dysregulated metabolites, such as NAD , NADP , FMN, fumaric acid, malic acid, and glutathione, was almost identical in both patients.