Inborn errors in fatty-acid metabolism: Living on the edge

Dynamic modeling showed that the topology of fatty-acid betaoxidation makes this pathway intrinsically vulnerable to substrate overload: at a high influx of palmitoyl-CoA into the pathway the flux dropped and intermediate CoA-esters accumulated extremely(Van Eunen et al., 2013 PLoS Comput Biol). We show here that inborn errors in fatty-acid metabolism aggravate the risk of amitochondrial catastrophe.We applied the previously constructed dynamic model to study the impact of multiple acyl-CoA dehydrogenase deficiency(MADD) and medium-chain acyl-CoA dehydrogenase deficiency(MCADD) on the kinetics of fatty acid oxidation. We explored the relation between the deficiencies and metabolite profiles and calculated which profiles might enhance the risk of pathway overload. MADD patients show accumulation of acylcarnitines acrossall chain lengths. In contrast, MCADD patients accumulate the medium-chain acylcarnitines. A linear non-competition model could not explain this, as it predicted exclusive accumulation of longer chain-length metabolites in MADD. This provides the first experimental evidence that molecular competition at the enzyme level is physiologically relevant for fatty-acid oxidation. Subsequently,this more realistic competition model was fitted to either mouse liver data or to disease-specific patient plasma data. When the substrate concentration was varied, both MADD and MCADD enhanced the accumulation of intermediate metabolite sand the flux declined already at lower substrate concentrations compared to the model without enzyme deficiencies.We hypothesize that the pathway structure of the beta-oxidationin which substrates compete for enzymes, is at the basis of the disease phenotypes associated with enzyme deficiencies.