αKG) bidirectionally and is therefore important for metabolic rewiring in hypoxic conditions and in case of mitochondrial dysfunction when reductive glutaminolysis (red pathway) is the prominent carbon source for citrate formation. (B) IDH2 in vitro activity assay in presence of Ciprofloxacin. Partial, but concentration-dependent inhibition in a physiologically relevant range was detected. The mean and SD of 4 replicates per condition is plotted. The graph is representative of three independent experiments. (C) Mitochondrial NADPH levels are decreased by approx. 25% after incubation of PDL-hTERT cells with Ciprofloxacin (7.5 μM, 6 h) in line with the in vitro inhibition of the forward oxidative reaction of IDH2. To prevent the onset of ETC dysregulation in line with our proteomic data (compare figure 1, S1,2,4) the lower concentration was deliberately chosen for this time point (average and mean of 3 independent experiments plotted, unpaired twotailed t-test, P-value <0.001). (D) Prolonged incubation, especially with the higher Ciprofloxacin concentration (75 µM, 3 days) resulted in elevated mitochondrial NADPH levels in PDL-hTERT cells, potentially as a result of the inhibition of the reverse reductive carboxylation reaction of IDH2 that is reported to be prominent in settings of mitochondrial dysfunction (average and mean of 3 independent experiments plotted). In the bar plots in B, C and D the statistical relevance based on one-way ANOVA with Dunnett´s multiple comparison test is depicted (ns meaning P-value > 0.05, * P-value ≤ 0.05, ** P-value ≤ 0.01, *** P-value ≤ 0.001, **** P-value ≤ 0.0001).