1. A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria.
- Author
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Phua YL, D'Annibale OM, Karunanidhi A, Mohsen AW, Kirmse B, Dobrowolski SF, and Vockley J
- Subjects
- Humans, Ketoglutaric Acids metabolism, Energy Metabolism drug effects, Energy Metabolism genetics, Mitochondria drug effects, Mitochondria metabolism, Mitochondria genetics, Metabolomics, Exome Sequencing, Citrate (si)-Synthase metabolism, Citrate (si)-Synthase genetics, Brain Diseases, Metabolic, Inborn drug therapy, Brain Diseases, Metabolic, Inborn genetics, Brain Diseases, Metabolic, Inborn metabolism, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Brain Diseases, Metabolic drug therapy, Brain Diseases, Metabolic genetics, Brain Diseases, Metabolic metabolism, Brain Diseases, Metabolic pathology, Multiomics, Mitochondrial Proteins, Organic Anion Transporters, Phenylbutyrates pharmacology, Phenylbutyrates therapeutic use, Fibroblasts metabolism, Fibroblasts drug effects, Glutarates metabolism
- Abstract
Purpose: To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene., Methods: Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing., Results: In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink., Conclusion: Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2024
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