Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia
- 15 September 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (611), eabf5965
- https://doi.org/10.1126/scitranslmed.abf5965
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 prevents an increase in CoA biosynthesis to alleviate CoASH sequestration. PZ-3022 is an allosteric PanK activator that counteracts C3-CoA inhibition. PZ-3022 therapy increased hepatic CoASH and C2-CoA and decreased C3-CoA in the PA mouse model, leading to improved intracellular C3:C2-CoA and plasma C3:C2-carnitine ratios. Elevated urinary malate is a major component of the metabolic signature for TCA cycle dysfunction in the PA mouse, and the 80% reduction in urine malate by PZ-3022 therapy indicates the restoration of mitochondrial function. Thus, CoASH sequestration in PA leads to reduced TCA cycle activity that is relieved by PZ-3022, providing preclinical proof of concept for PanK activators as a therapy to attenuate the underlying mitochondrial defect in PA.Keywords
This publication has 99 references indexed in Scilit:
- In Vivo Neurochemical Monitoring Using Benzoyl Chloride Derivatization and Liquid Chromatography–Mass SpectrometryAnalytical Chemistry, 2011
- Modulation of Pantothenate Kinase 3 Activity by Small Molecules that Interact with the Substrate/Allosteric Regulatory DomainCell Chemical Biology, 2010
- A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cellsProceedings of the National Academy of Sciences of the United States of America, 2010
- MolProbity: all-atom structure validation for macromolecular crystallographyActa crystallographica. Section D, Structural biology, 2009
- Short-Term Rescue of Neonatal Lethality in a Mouse Model of Propionic Acidemia by Gene TherapyHuman Gene Therapy, 2009
- Chemical Knockout of Pantothenate Kinase Reveals the Metabolic and Genetic Program Responsible for Hepatic Coenzyme A HomeostasisCell Chemical Biology, 2007
- Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitineProceedings of the National Academy of Sciences of the United States of America, 2007
- Solving structures of protein complexes by molecular replacement withPhaserActa crystallographica. Section D, Structural biology, 2006
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976