Lactate Metabolism in Human Health and Disease

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2022 Sep 1

PMID 36050306

Authors

Xiaolu Li

Yanyan Yang

Bei Zhang

Xiaotong Lin

Xiuxiu Fu

Yi An

Yulin Zou

Jian-Xun Wang

Zhibin Wang

Tao Yu

Affiliations

Soon will be listed here.

Abstract

The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism, as identified by studies on the Warburg effect. The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells, organs and tissues. Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao's research group in 2019. Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation, neural excitation, inflammation and other biological processes. An indispensable substance for various physiological cellular functions, lactate plays a regulatory role in different aspects of energy metabolism and signal transduction. Therefore, a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research. This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes, as well as a comprehensive overview of the effects of lactylation in various diseases, particularly inflammation and cancer.

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References

Ferguson B, Rogatzki M, Goodwin M, Kane D, Rightmire Z, Gladden L . Lactate metabolism: historical context, prior misinterpretations, and current understanding. Eur J Appl Physiol. 2018; 118(4):691-728. DOI: 10.1007/s00421-017-3795-6. View

Brooks G . Lactate shuttles in nature. Biochem Soc Trans. 2002; 30(2):258-64. DOI: 10.1042/. View

Brooks G . Cell-cell and intracellular lactate shuttles. J Physiol. 2009; 587(Pt 23):5591-600. PMC: 2805372. DOI: 10.1113/jphysiol.2009.178350. View

Daw C, Ramachandran K, Enslow B, Maity S, Bursic B, Novello M . Lactate Elicits ER-Mitochondrial Mg Dynamics to Integrate Cellular Metabolism. Cell. 2020; 183(2):474-489.e17. PMC: 7572828. DOI: 10.1016/j.cell.2020.08.049. View

Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z . HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications. Cell Rep. 2020; 33(10):108487. DOI: 10.1016/j.celrep.2020.108487. View

Felmlee M, Jones R, Rodriguez-Cruz V, Follman K, Morris M . Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease. Pharmacol Rev. 2020; 72(2):466-485. PMC: 7062045. DOI: 10.1124/pr.119.018762. View

Liberti M, Locasale J . The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem Sci. 2016; 41(3):211-218. PMC: 4783224. DOI: 10.1016/j.tibs.2015.12.001. View

Vaupel P, Multhoff G . Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol. 2020; 599(6):1745-1757. DOI: 10.1113/JP278810. View

Li X, Jiang Y, Meisenhelder J, Yang W, Hawke D, Zheng Y . Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis. Mol Cell. 2016; 61(5):705-719. PMC: 4888784. DOI: 10.1016/j.molcel.2016.02.009. View

10.

Teng R, Liu Z, Tang H, Zhang W, Chen Y, Xu R . HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells. Redox Biol. 2019; 24:101218. PMC: 6526248. DOI: 10.1016/j.redox.2019.101218. View

11.

Certo M, Tsai C, Pucino V, Ho P, Mauro C . Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol. 2020; 21(3):151-161. DOI: 10.1038/s41577-020-0406-2. View

12.

Chen Z, Liu M, Li L, Chen L . Involvement of the Warburg effect in non-tumor diseases processes. J Cell Physiol. 2017; 233(4):2839-2849. DOI: 10.1002/jcp.25998. View

13.

Dabral S, Muecke C, Valasarajan C, Schmoranzer M, Wietelmann A, Semenza G . A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nat Commun. 2019; 10(1):2130. PMC: 6513860. DOI: 10.1038/s41467-019-10044-z. View

14.

Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y . Metabolic regulation of gene expression by histone lactylation. Nature. 2019; 574(7779):575-580. PMC: 6818755. DOI: 10.1038/s41586-019-1678-1. View

15.

Tong Y, Guo D, Lin S, Liang J, Yang D, Ma C . SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells. Mol Cell. 2021; 81(11):2303-2316.e8. DOI: 10.1016/j.molcel.2021.04.002. View

16.

Guo Y, Zhang X, Zhao Z, Lu H, Ke B, Ye X . NF- B/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis. Acta Pharm Sin B. 2020; 10(5):825-836. PMC: 7276689. DOI: 10.1016/j.apsb.2020.02.005. View

17.

Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H . Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell. 2011; 42(6):719-30. PMC: 4879880. DOI: 10.1016/j.molcel.2011.04.025. View

18.

Galvan-Pena S, Carroll R, Newman C, Hinchy E, Palsson-McDermott E, Robinson E . Malonylation of GAPDH is an inflammatory signal in macrophages. Nat Commun. 2019; 10(1):338. PMC: 6338787. DOI: 10.1038/s41467-018-08187-6. View

19.

Harmer A, Chisholm D, McKenna M, Hunter S, Ruell P, Naylor J . Sprint training increases muscle oxidative metabolism during high-intensity exercise in patients with type 1 diabetes. Diabetes Care. 2008; 31(11):2097-102. PMC: 2571053. DOI: 10.2337/dc08-0329. View

20.

Levy B, Gibot S, Franck P, Cravoisy A, Bollaert P . Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. 2005; 365(9462):871-5. DOI: 10.1016/S0140-6736(05)71045-X. View