Journal of Molecular Medicine

, Volume 90, Issue 12, pp 1497–1504 | Cite as

Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism

  • Ruth Belostotsky
  • James Jonathon Pitt
  • Yaacov Frishberg
Original Article


Perturbations in glyoxylate metabolism lead to the accumulation of oxalate and give rise to primary hyperoxalurias, recessive disorders characterized by kidney stone disease. Loss-of-function mutations in HOGA1 (formerly DHDPSL) are responsible for primary hyperoxaluria type III. HOGA1 is a mitochondrial 4-hydroxy-2-oxoglutarate aldolase catalyzing the fourth step in the hydroxyproline pathway. We investigated hydroxyproline metabolites in the urine of patients with primary hyperoxaluria type III using gas chromatography–mass spectroscopy. Significant increases in concentrations of 4-hydroxy-2-oxoglutarate and its precursor and derivative 4-hydroxyglutamate and 2,4-dihydroxyglutarate, respectively, were found in all patients as compared to carriers of the corresponding mutations or healthy controls. Despite a functional block in the conversion of hydroxyproline to glyoxylate—the immediate precursor of oxalate—the production of oxalate increases. To explain this apparent contradiction, we propose a model of glyoxylate compartmentalization in which cellular glyoxylate is normally prevented from contact with the cytosol where it can be oxidized to oxalate. We propose that HOGA1 deficiency results in the accumulation of 4-hydroxy-2-oxoglutarate in the mitochondria and its transport into the cytosol where it is converted to glyoxylate by a different cytosolic aldolase. In human hepatocyte cell lines, we detected a cytosolic 4-hydroxy-2-oxoglutarate aldolase activity not due to HOGA1. These studies provide a diagnostic tool for primary hyperoxaluria type III and shed light on glyoxylate metabolism and the pathogenesis of primary hyperoxalurias.


HOGA1 PHIII Hydroxyproline pathway Glyoxylate Oxalate DHDPSL 



The authors are indebted to Prof. Hanna Mandel for helpful advice. Sections of this work were supported by the Victorian Government's Operational Infrastructure Support Program.

Conflict of interest

The authors declare that no conflict of interest exists.

Supplementary material

109_2012_930_MOESM1_ESM.pdf (58 kb)
ESM 1 (PDF 58 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ruth Belostotsky
    • 1
  • James Jonathon Pitt
    • 2
  • Yaacov Frishberg
    • 1
    • 3
  1. 1.Division of Pediatric NephrologyShaare Zedek Medical CenterJerusalemIsrael
  2. 2.VCGS Pathology, Murdoch Childrens Research InstituteRoyal Children’s HospitalParkvilleAustralia
  3. 3.Hadassah-Hebrew University School of MedicineJerusalemIsrael

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