Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney

Garrett Brinkley, Hyeyoung Nam, Eunhee Shim, Richard Kirkman, Anirban Kundu, Suman Karki, Yasaman Heidarian, Jason M. Tennessen, Juan Liu, Jason W. Locasale, Tao Guo, Shi Wei, Jennifer Gordetsky, Teresa L. Johnson-Pais, Devin Absher, Dinesh Rakheja, Anil K. Challa, Sunil Sudarshan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite L2HGDH being highly expressed in the kidney, its role in renal metabolism has not been explored. Here, we report our findings utilizing a novel CRISPR/Cas9 murine knockout model, with a specific focus on the role of L2HGDH in the kidney. Histologically, L2hgdh knockout kidneys have no demonstrable histologic abnormalities. However, GC-MS metabolomics demonstrates significantly reduced levels of the TCA cycle intermediate succinate in multiple tissues. Isotope labeling studies with [U-13C] glucose demonstrate that restoration of L2HGDH in renal cancer cells (which lowers L-2HG) leads to enhanced incorporation of label into TCA cycle intermediates. Subsequent biochemical studies demonstrate that L-2HG can inhibit the TCA cycle enzyme α-ketoglutarate dehydrogenase. Bioinformatic analysis of mRNA expression data from renal tumors demonstrates that L2HGDH is co-expressed with genes encoding TCA cycle enzymes as well as the gene encoding the transcription factor PGC-1α, which is known to regulate mitochondrial metabolism. Restoration of PGC-1α in renal tumor cells results in increased L2HGDH expression with a concomitant reduction in L-2HG levels. Collectively, our analyses provide new insight into the physiological role of L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.

Original languageEnglish (US)
Article numberdmm045898
JournalDMM Disease Models and Mechanisms
Volume13
Issue number11
DOIs
StatePublished - Nov 27 2020

Keywords

  • L-2-hydroxyglutarate
  • L-2-hydroxyglutarate dehydrogenase
  • PPARGC1A
  • TCA cycle

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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