Figure 7. The response to metformin depends on whether substrate utilization in the mitochondria is flexible.

A. Schematic of substrate utilization. The adaptive pathways under mitochondrial stress are highlighted in green color. OAA: oxaloacetate, Keto acids: ketoleucine/ketoisoleucine. B. Reductive glutaminolysis activity as represented by the fraction of ¹³C enriched citrate isotopologue (M+5) from cells treated with ¹³C-glutamine in different medium conditions. C. Pyruvate carboxylase activity as estimated by the fraction of malate (M+3) from cells treated with ¹³C-glucose in different medium conditions. D. Ketoleucine/ketoisoleucine levels in different media conditions, representing BCAA oxidation. E. Representative metabolite enrichment pattern from U-¹³C pyruvate treated cells. F. Scheme of coupled transamination reactions demonstrating stoichiometric alpha-ketoglutarate generation from alanine labeling. G. Model of resistant and sensitive response to metformin treatment. * p<0.05, ** p<0.01 Error bars obtained from SEM of n=3 independent measurements.