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. 2016 Aug 9;7:12317. doi: 10.1038/ncomms12317

Figure 1. Effects of mitochondrial complex II stimulation by the succinate prodrug NV189.

Figure 1

(a) Structures of NV118, NV189 and NV241, succinate highlighted in red. (b) Respiration in platelets (plts) with rotenone-induced mitochondrial complex I (CI) inhibition. (c) ATP-generating respiration in platelets. (d) Mitochondrial membrane potential in complex I-inhibited platelets, ratio of basal TMRM fluorescence, n=4. (e) Respiration in platelets with FCCP-induced uncoupling. (f) Respiration in digitonin-permeabilized platelets. (g) Effect on respiration in platelets with addition of the cell-permeable complex II inhibitor NV161, * indicate significant difference between NV161 and vehicle, n=4. (h) Structure of NV161, malonate highlighted in red. (i) Respiration in peripheral blood mononuclear cells (PBMCs) with rotenone-induced CI inhibition, n=4. (j) Convergent respiration in PBMCs, n=4, * indicate significant difference between pre and post dosing. (k) Respiration in human heart muscle fibres (HHMFs), n=5. (l) Lactate:pyruvate ratio in PBMCs at baseline, after rotenone CI inhibition and after treatment with NV189, n=4. * indicates significant difference using Friedmans non-parametric paired test with Dunn's multiple comparisons test of all groups against control. For three data points, pyruvate was below detection limit and the estimated lower-quantification limit was used for calculating the ratio. (m) Lactate accumulation in 2 ml buffer containing 400 × 106 platelets, incubated with or without rotenone, antimycin A and NV189, n=5. (n) Lactate production in platelets, data quantification from previous panel. Mean with 95% confidence interval. All respirometric experiments in human platelets were performed with n=6 individuals donors if not otherwise stated. All data presented as mean and s.e. if not otherwise stated. In all experiments, blood cells from separate donors are used for each n. *P<0.05, **P<0.01, ***P<0.001 (two-tailed paired or unpaired Student's t-test as appropriate, difference between test compound and control if not otherwise stated).