Jason Locasale

Overview:

Our research interests are in three interconnected areas:  1) Quantitative and computational biology of metabolism. 2) The role of diet and pharmacological therapeutics in shaping metabolic pathways in health and cancer.  3) The interaction of metabolism and epigenetics.  Each of these synergistic areas utilizes the metabolomics technologies we develop along with our expertise in computational and molecular biology.

Positions:

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of Duke Molecular Physiology Institute

Duke Molecular Physiology Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.A. 2003

Rutgers University New Brunswick

Ph.D. 2008

Massachusetts Institute of Technology

Publications:

Author Correction: The evolving metabolic landscape of chromatin biology and epigenetics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Authors
Dai, Z; Ramesh, V; Locasale, JW
MLA Citation
Dai, Ziwei, et al. “Author Correction: The evolving metabolic landscape of chromatin biology and epigenetics.Nat Rev Genet, vol. 21, no. 12, Dec. 2020, p. 782. Pubmed, doi:10.1038/s41576-020-00291-y.
URI
https://scholars.duke.edu/individual/pub1460830
PMID
32978605
Source
pubmed
Published In
Nat Rev Genet
Volume
21
Published Date
Start Page
782
DOI
10.1038/s41576-020-00291-y

Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion.

The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
Authors
Yu, Y-R; Imrichova, H; Wang, H; Chao, T; Xiao, Z; Gao, M; Rincon-Restrepo, M; Franco, F; Genolet, R; Cheng, W-C; Jandus, C; Coukos, G; Jiang, Y-F; Locasale, JW; Zippelius, A; Liu, P-S; Tang, L; Bock, C; Vannini, N; Ho, P-C
MLA Citation
Yu, Yi-Ru, et al. “Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion.Nat Immunol, vol. 21, no. 12, Dec. 2020, pp. 1540–51. Pubmed, doi:10.1038/s41590-020-0793-3.
URI
https://scholars.duke.edu/individual/pub1462204
PMID
33020660
Source
pubmed
Published In
Nat Immunol
Volume
21
Published Date
Start Page
1540
End Page
1551
DOI
10.1038/s41590-020-0793-3

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

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.
Authors
Brinkley, G; Nam, H; Shim, E; Kirkman, R; Kundu, A; Karki, S; Heidarian, Y; Tennessen, JM; Liu, J; Locasale, JW; Guo, T; Wei, S; Gordetsky, J; Johnson-Pais, TL; Absher, D; Rakheja, D; Challa, AK; Sudarshan, S
MLA Citation
Brinkley, Garrett, et al. “Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney.Dis Model Mech, vol. 13, no. 11, Nov. 2020. Pubmed, doi:10.1242/dmm.045898.
URI
https://scholars.duke.edu/individual/pub1460831
PMID
32928875
Source
pubmed
Published In
Dis Model Mech
Volume
13
Published Date
DOI
10.1242/dmm.045898

SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease.

Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.
Authors
Gut, P; Matilainen, S; Meyer, JG; Pällijeff, P; Richard, J; Carroll, CJ; Euro, L; Jackson, CB; Isohanni, P; Minassian, BA; Alkhater, RA; Østergaard, E; Civiletto, G; Parisi, A; Thevenet, J; Rardin, MJ; He, W; Nishida, Y; Newman, JC; Liu, X; Christen, S; Moco, S; Locasale, JW; Schilling, B; Suomalainen, A; Verdin, E
MLA Citation
Gut, Philipp, et al. “SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease.Nat Commun, vol. 11, no. 1, Nov. 2020, p. 5927. Pubmed, doi:10.1038/s41467-020-19743-4.
URI
https://scholars.duke.edu/individual/pub1465634
PMID
33230181
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
5927
DOI
10.1038/s41467-020-19743-4

Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway.

Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in metabolism, DNA repair, and aging. However, how NAD metabolism is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer resistance to inhibitors of NAMPT, the rate-limiting enzyme in the amidated NAD salvage pathway, in cancer cells and xenograft tumors. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. Using stable isotope tracing and microbiota-depleted mice, we demonstrate that this bacteria-mediated deamidation contributes substantially to the NAD-boosting effect of oral nicotinamide and nicotinamide riboside supplementation in several tissues. Collectively, our findings reveal an important role of bacteria-enabled deamidated pathway in host NAD metabolism.
Authors
Shats, I; Williams, JG; Liu, J; Makarov, MV; Wu, X; Lih, FB; Deterding, LJ; Lim, C; Xu, X; Randall, TA; Lee, E; Li, W; Fan, W; Li, J-L; Sokolsky, M; Kabanov, AV; Li, L; Migaud, ME; Locasale, JW; Li, X
MLA Citation
Shats, Igor, et al. “Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway.Cell Metab, vol. 31, no. 3, Mar. 2020, pp. 564-579.e7. Pubmed, doi:10.1016/j.cmet.2020.02.001.
URI
https://scholars.duke.edu/individual/pub1434091
PMID
32130883
Source
pubmed
Published In
Cell Metab
Volume
31
Published Date
Start Page
564
End Page
579.e7
DOI
10.1016/j.cmet.2020.02.001