Fig. 5: Cysteine deficiency leads to metabolic inefficiency by depleting CoA.

a, CoA structure and pathways for its production and degradation. PPanSH, phosphopantetheine; PanSH, pantetheine; PPan, phosphopantothenate; TCA, tricarboxylic acid. b–d, CoA levels in the liver (b) and muscle (c) at day 2 and in the liver at day 7 (d) from Cse^+/− and Cse^−/− mice on a no-Cys diet. n ≥ 4 for all groups. e,f, Quantification (e) and glycolytic pathway schematic (f) of metabolite changes in the urine and liver of Cse^−/− mice compared with Cse^+/− mice on a no-Cys diet. n = 6 (Cse^+/−, urine), n = 7 (Cse^−/−, urine), n = 4 (Cse^+/−, liver) and n = 3 (Cse^−/−, liver). KB, ketone bodies. P < 0.05 was observed for all metabolites, except for 3-hydroxybutyrate (P = 0.0891) (e). For f, liver glycolytic intermediates that are upregulated in KO are shown in red, with P < 0.05 and log₂[fold change] in brackets. g, O₂ consumption by mice that were provided with galactose (gal) or glucose (glu) as a sole carbon source after feeding on a no-Cys diet. n = 4. h, Weight measurements of Cse^+/− and Cse^−/− mice on a no-B5 diet or a no-B5 and no-Cys diet. n = 4 per group. i, Changes in Vnn1 mRNA expression levels across tissues at day 2 of a CR no-Cys diet (Supplementary Tables 2–4). j, Urine B5 levels in Cse^+/− and Cse^−/− mice at day 2 of a CR no-Cys diet. a.u., arbitrary units. k, The expected levels of various cysteine-containing metabolites under different conditions. l, Weight measurements of Cse^−/− mice after 7 days of a no-Cys diet followed by 7 days of either a control diet or a no-B5 diet. n = 5 per group. m,n, Liver (m) and muscle (n) CoA levels in mice on day 14 from the experiment shown in l. n = 8 (Cse^+/−) and n = 9 (Cse^−/−) in m and n. o, Model summary. The diagrams in a, g, k and o were created using BioRender. CoA structure in a obtained from https://www.rcsb.org/chemical-sketch (Marvin JS by Chemaxon). Statistical analysis was performed using unpaired t-tests (b–f, j, m and n). Data are mean ± s.e.m.

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