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

Brinkley, Garrett and Nam, Hyeyoung and Shim, Eunhee and Kirkman, Richard and Kundu, Anirban and Karki, Suman and Heidarian, Yasaman and Tennessen, Jason M. and Liu, Juan and Locasale, Jason W. and Guo, Tao and Wei, Shi and Gordetsky, Jennifer and Johnson-Pais, Teresa L. and Absher, Devin and Rakheja, Dinesh and Challa, Anil K. and Sudarshan, Sunil (2020) Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney. Disease Models & Mechanisms, 13 (11). Art. No. dmm045898. ISSN 1754-8403. https://resolver.caltech.edu/CaltechAUTHORS:20210121-102554077

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1242/dmm.045898DOIArticle
https://dmm.biologists.org/lookup/doi/10.1242/dmm.045898.supplementalPublisherSupplementary Information
ORCID:
AuthorORCID
Brinkley, Garrett0000-0003-2622-3416
Nam, Hyeyoung0000-0002-9964-728X
Kirkman, Richard0000-0002-4212-0751
Kundu, Anirban0000-0003-0621-9989
Heidarian, Yasaman0000-0002-7134-7859
Tennessen, Jason M.0000-0002-3527-5683
Locasale, Jason W.0000-0002-7766-3502
Gordetsky, Jennifer0000-0002-0745-2160
Johnson-Pais, Teresa L.0000-0001-7580-1206
Absher, Devin0000-0003-4405-1646
Rakheja, Dinesh0000-0001-6888-7902
Challa, Anil K.0000-0002-3633-3304
Sudarshan, Sunil0000-0001-7257-6277
Additional Information:© 2020. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Received May 23, 2020; Accepted September 2, 2020. We acknowledge the assistance of the UAB Transgenic and Genetically Engineered Models Core and Comparative Pathology Laboratory. The research reported in this article was supported by the National Institutes of Health (R01CA200653 and I01BX002930 to S.S.; F30CA232397 to G.B; T32GM008361) and in part by the University of Alabama at Birmingham O'Neal Comprehensive Cancer Center (P30CA013148). Tumor genotyping was supported in part by the University of Texas Health Science Center at San Antonio Mays Cancer Center Genomics Shared Resource Facility (P30CA054174). J.M.T. is supported by a Maximizing Investigators’ Research Award from the National Institute of General Medical Sciences (R35GM119557). The authors declare no competing or financial interests. Author contributions: Conceptualization: G.B., S.S.; Methodology: G.B.; Formal analysis: G.B., E.S., J.M.T., J.L., J.W.L., T.G., S.W., J.G., T.L.J.-P., D.A., D.R.; Investigation: G.B., H.N., E.S., R.K., A.K., S.K., Y.H., J.L., T.G., T.L.J.-P.; Resources: R.K., A.K.C.; Writing - original draft: G.B., S.S.; Writing - review & editing: G.B., S.S.; Supervision: S.S.; Funding acquisition: S.S.
Funders:
Funding AgencyGrant Number
NIHR01CA200653
NIHI01BX002930
NIH Postdoctoral FellowshipF30CA232397
NIH Predoctoral FellowshipT32GM008361
NIHP30CA013148
NIHP30CA054174
NIHR35GM119557
Subject Keywords:L-2-hydroxyglutarate; L-2-hydroxyglutarate dehydrogenase; TCA cycle; PPARGC1A
Issue or Number:11
Record Number:CaltechAUTHORS:20210121-102554077
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210121-102554077
Official Citation: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. Disease Models & Mechanisms 2020 13: dmm045898 doi: 10.1242/dmm.045898 Published 27 November 2020
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107632
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Jan 2021 19:26
Last Modified:21 Jan 2021 19:26

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