Skip to main content
. 2024 Jul 18;9(16):e177152. doi: 10.1172/jci.insight.177152

Figure 6. NAD+ precursor treatment amplifies glutathione synthesis in shFxn hearts.

Figure 6

(A) Plasma nicotinamide and 2-PY levels are increased in treated mice. (B) NAD+ and NADP+ are significantly depleted in shFxn hearts, with recovery of NADP with NMN treatment. NADH and NADPH levels are unchanged with loss of frataxin and with precursor treatment. (C) Heatmap of metabolites significantly changed with NR and NMN treatment (pooled analysis). Bolded metabolites were significantly modified by depletion of frataxin. (D) Using list in C, Metaboanalyst identified glutathione metabolism as significantly changed by treatment in shFxn hearts. (E) Glutathione related metabolites are altered in shFxn mice and treated mice. [Box Plots: Metabolite-[group:mean, lower, upper]] [Glutathione-[WT:1, 0.46, 1.97; shFxn:1.57, 1.33, 1.71; NR:2.189, 2.04, 2.39; NMN:2.40, 1.24, 2.97] Glutathione Disulfide-[WT:1, 0.68, 1.16; shFxn:1.02, 0.95, 1.11; NR:1.35, 1.23, 1.43; NMN:1.49, 1.25, 2.00] γ-glutamylcysteine-[WT:1, 0.71, 1.52; shFxn:0.39, 0.22, 0.53; NR:0.72, 0.54, 0.83; NMN:0.72, 0.39, 1.00] γ-glutamyltaurine-[WT:1, 0.17, 2.97; shFxn:3.27, 2.70, 3.87; NR:2.05, 0.84, 2.81; NMN:1.95, 1.32, 2.77] Glycine-[WT:1, 0.86, 1.14; shFxn:1.21, 1.09, 1.35; NR:1.34, 1.02, 1.55; NMN:1.54, 1.185, 1.94]. Brackets indicate pairwise comparisons with P values indicated for several that did not reach significance. (F) Model representing metabolite changes in glutathione synthesis pathways. Left arrow is direction in shFxn vs. WT mice, right arrow with glow is direction in shFxn vs. treated mice, red symbols are upregulated in shFxn mice, blue symbols are downregulated, and green are unchanged. A, B, and E, n = 6–17, 1-way ANOVA, Fisher’s LSD test); C, n = 6–17, normalized ion value, 2-tailed t test (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001).