Loss of pyruvate carboxylase suppresses lethality in propionic acidemia

Inborn errors in propionyl-CoA carboxylase cause life-threatening propionic acidemia. To understand the contribution of propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific Pcca knockout mouse models. The inducible whole-body loss of Pcca results in acute metabolic decompensation like the inborn error. The liver-specific loss of Pcca recapitulates these adverse effects, demonstrating the centrality of the liver to systemic disease. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Strikingly, the lethality of Pcca knockout (KO) mice is reversed by simultaneously inhibiting pyruvate carboxylase (Pcx). Most metabolites suspected as deleterious in propionic acidemia are exacerbated in liver-specific Pcca;Pcx double KO mice with the exception of methylcitrate, suggesting a role of this metabolite in systemic toxicity. These data clarify relevant toxic biomarkers and suggest that rebalancing hepatic TCA cycle metabolism is critical to mitigate the adverse effects from alternative propionyl-CoA metabolic pathways.