Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia.

ABSTRACT: Propionic acidemia (PA) is a rare autosomal-recessive metabolic disease that arises from mutations in propionyl-CoA (C3-CoA) carboxylase. Reduced enzyme activity slows C3-CoA metabolism, leading to an elevated plasma C3:C2-carnitine ratio, the hallmark biomarker of PA. The metabolic imbalances experienced in PA are however poorly defined. Here, we used a hypomorphic PA mouse model to demonstrate that C3-CoA accumulation in liver reduced non-esterified CoA (CoASH) and acetyl-CoA (C2-CoA). Tricarboxylic acid (TCA) cycle intermediates that are normally metabolized instead accumulated in urine, providing direct evidence for compromised mitochondrial function in PA. Pantothenate kinase (PanK) is known to catalyze the rate-controlling step in CoA biosynthesis, and its inhibition by C3-CoA preven

SUBMITTER: Subramanian C 

PROVIDER: S-EPMC8830021 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature