Metabolic rerouting of valine and isoleucine oxidation increases survival in zebrafish models of disorders of propionyl-CoA metabolism

Abstract Branched-chain amino acid (BCAA) oxidation is a multistep process leading to the formation of acetyl-CoA and propionyl-CoA. The syndromes associated with disturbed BCAA oxidation are clinically and biochemically heterogenous. While the common organic acidemias, propionic (PA) and methylmalonic acidemia (MMA), arise from deficient activity of propionyl-CoA carboxylase and methylmalonyl-CoA mutase and are life-threatening conditions with limited treatment options, isobutyryl-CoA dehydrogenase (IBD), and 2-methylbutyryl-CoA dehydrogenase (2-MBD) deficiencies manifest as biochemical traits, with no associated symptoms or consistent metabolic phenotypes. To assess whether the proximal interruption of valine and isoleucine oxidation might represent an approach to treat MMA and PA, we investigated the effects of loss of function of acad8 (encoding IBD) and acadsb (encoding 2-MBD), singly and doubly, on biochemical and morphological findings of zebrafish models of pccb-related propionic acidemia (PA) and mmut methylmalonic acidemia (MMA). Although acad8−/−;acadsb−/− double mutants showed growth failure and early mortality, the proximal interruption of valine and isoleucine oxidation in double (pccb/acad8, pccb/acadsb, mmut/acad8, mmut/acadsb) and triple (pccb/acad8/acadsb, mmut/acad8/acadsb) homozygous mutants improved pccb−/− and mmut−/− survival and reduced propionate-derived toxic metabolites, supporting the rationale for pursuing modulation of IBD and 2-MBD activity as a strategy to reduce the metabolic load and improve clinical outcomes in PA and MMA.