Fig. 4: A proposed metabolic pathway that links fatty acid β-oxidation to ketogenesis in starvation-induced NRP mycobacteria.

a Heatmaps show that starvation causes a coordinated transcriptional and translational upregulation of enzymes involved in fatty acid β-oxidation, with both transcription and translation downregulated upon resuscitation. The heatmap key is described below. This behavior underscores the importance of fatty acid metabolism for starvation-induced NRP in BCG. Upregulated lipQ, lipT, lipV, and lipY release fatty acids that are converted to fatty acid-CoA by fatty acid ligases (FadD; fadD8, fadD12, fadD35) as the entry point for β-oxidation. Subsequently, fatty acid oxidation is mediated by fadE7, fadE9, fadE27, and fadE35, 3-hydroxyl oxidation by BCG_3587, and hydration by echA5, echA7, and echA19, with the terminal thiolysis performed by fadA, fadA4, and fadA5. b Acetyl-CoA from fatty acid β-oxidation is then facilitates the starvation-induced increase in b-hydroybutryte (BHB; Fig. 3e). Starvation-upregulated ketothiolases (fadA, fadA4, fadA5) serve as acetyl-coA acetyltransferases to condense 2 acetyl-CoA molecules to acetoacetyl-CoA, which is converted to acetoacetate by upregulated succinyl-CoA:3-ketoacid-CoA transferase (scoA, scoB) and to BHB by upregulated 3-hydroxybutyrate dehydrogenase (BCG_1967c). Proteins levels for BCG_3587, ScoA, and ScoB were not quantified. Key: Relative transcript and proteins abundances are visualized after counts are normalized to their levels at Log (hence not visualized, crossed boxes) and log₂ transformed. Heatmaps are used to represent mRNA (blue–orange scale) and protein (purple–yellow scale) levels at various time points (S4, S10, S20, and R6) in order with colors assigned based on their Z-scores across the time points. With yellow (protein) or orange (mRNA) for positive Z-scores and purple (protein) and blue (mRNA) for negative Z-scores. As an illustration, results for the chaperone HspX are shown. See Supplementary Data 4 for the source data used in these graphs.