L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule may have physiologic 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 being highly expressed in the kidney, L2HGDH's 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 KO 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 if L-2HG levels. Collectively, our studies provide new insight into the physiologic role for L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.
Teleological Role of L-2-Hydroxyglutarate Dehydrogenase in the Kidney
Present address: Division of Biology and Biological Engineering, Caltech University
Currently Viewing Accepted Manuscript - Newer Version Available
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; Teleological Role of L-2-Hydroxyglutarate Dehydrogenase in the Kidney. Dis Model Mech 2020; dmm.045898. doi: https://doi.org/10.1242/dmm.045898
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