Propionyl-CoA carboxylase pcca-1 and pccb-1 gene deletions in Caenorhabditis elegans globally impair mitochondrial energy metabolism

AbstractPropionic acidemia (PA) is a classical inborn error of metabolism with high morbidity that results from the inability of the propionyl-CoA carboxylase (PCC) enzyme to convert propionyl-CoA to methylmalonyl-CoA. PA is inherited in an autosomal recessive fashion due to functional loss of both alleles of eitherPCCA orPCCB. These genes are highly conserved across evolutionarily diverse species and share extensive similarity withpcca-1 andpccb-1 in the nematode,Caenorhabditis elegans. Here, we report the global metabolic effects of deletion in a single PCC gene, eitherpcca-1 orpccb-1, inC. elegans. Animal lifespan was significantly reduced relative to wild-type worms in both mutant strains, although to a greater degree inpcca-1. Mitochondrial oxidative phosphorylation (OXPHOS) capacity and efficiency as determined by direct polarography of isolated mitochondria were also significantly reduced in both mutant strains. While in vivo quantitation of mitochondrial physiology was normal inpccb-1 mutants,pcca-1 deletion mutants had significantly increased mitochondrial matrix oxidant burden as well as significantly decreased mitochondrial membrane potential and mitochondrial content. Whole worm steady-state free amino acid profiling by UPLC revealed reduced levels in both mutant strains of the glutathione precursor cysteine, possibly suggestive of increased oxidative stress. Intermediary metabolic flux analysis by GC/MS with 1,6-13C2-glucose further showed both PCC deletion strai...
Source: Journal of Inherited Metabolic Disease - Category: Internal Medicine Source Type: research