Lactate metabolism is associated with mammalian mitochondria

ABSTRACT It is well established that lactate secreted by fermenting cells can be oxidized or used as a gluconeogenic substrate by other cells and tissues. It is generally assumed, however,

that within the fermenting cell itself, lactate is produced to replenish NAD+ and then is secreted. Here we explore the possibility that cytosolic lactate is metabolized by the mitochondria

of fermenting mammalian cells. We found that fermenting HeLa and H460 cells utilize exogenous lactate carbon to synthesize a large percentage of their lipids. Using high-resolution mass

spectrometry, we found that both 13C and 2-2H labels from enriched lactate enter the mitochondria. The lactate dehydrogenase (LDH) inhibitor oxamate decreased respiration of isolated

mitochondria incubated in lactate, but not of isolated mitochondria incubated in pyruvate. Additionally, transmission electron microscopy (TEM) showed that LDHB localizes to the

mitochondria. Taken together, our results demonstrate a link between lactate metabolism and the mitochondria of fermenting mammalian cells. Access through your institution Buy or subscribe

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GLUCOSE FEEDS THE TRICARBOXYLIC ACID CYCLE VIA EXCRETED ETHANOL IN FERMENTING YEAST Article 15 August 2022 WARBURG-ASSOCIATED ACIDIFICATION REPRESSES LACTIC FERMENTATION INDEPENDENTLY OF

LACTATE, CONTRIBUTION FROM REAL-TIME NMR ON CELL-FREE SYSTEMS Article Open access 18 October 2023 LACTATE: THE UGLY DUCKLING OF ENERGY METABOLISM Article 20 July 2020 REFERENCES * Lehninger,

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references ACKNOWLEDGEMENTS This work was supported by funding from the National Institutes of Health grants R01 ES022181 (G.J.P.), R21 CA191097-01A1 (G.J.P.), R01 HL118639-03 (R.W.G.), R01

DK091538 (P.A.C.), and R01 EB002058 (J.S.), as well as grants from the Alfred P. Sloan Foundation (G.J.P.), the Camille & Henry Dreyfus Foundation (G.J.P.), and the Pew Scholars Program

in the Biomedical Sciences (G.J.P.). We thank W. Beatty at Washington University's Molecular Microbiology Imaging Facility for acquiring the TEM images. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Chemistry, Washington University, St. Louis, Missouri, USA Ying-Jr Chen, Nathaniel G Mahieu, Manmilan Singh, Jacob Schaefer & Gary J Patti * Department of

Genetics, Washington University School of Medicine, St. Louis, Missouri, USA Xiaojing Huang & Stephen L Johnson * Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida,

USA Xiaojing Huang & Peter A Crawford * Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Richard W Gross & Gary J Patti Authors * Ying-Jr

Chen View author publications You can also search for this author inPubMed Google Scholar * Nathaniel G Mahieu View author publications You can also search for this author inPubMed Google

Scholar * Xiaojing Huang View author publications You can also search for this author inPubMed Google Scholar * Manmilan Singh View author publications You can also search for this author

inPubMed Google Scholar * Peter A Crawford View author publications You can also search for this author inPubMed Google Scholar * Stephen L Johnson View author publications You can also

search for this author inPubMed Google Scholar * Richard W Gross View author publications You can also search for this author inPubMed Google Scholar * Jacob Schaefer View author

publications You can also search for this author inPubMed Google Scholar * Gary J Patti View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

Y.-J.C. prepared samples, carried out biochemical assays, and performed LC/MS analyses. Y.-J.C., M.S., and J.S. performed NMR analyses. Y.-J.C., N.G.M., X.H., M.S., P.A.C., S.L.J., R.W.G.,

J.S., and G.J.P. contributed to experimental design and data interpretation. Y.-J.C., N.G.M., and G.J.P. wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Gary J Patti. ETHICS

DECLARATIONS COMPETING INTERESTS G.J.P. is a scientific advisory board member for Cambridge Isotope Laboratories, Tewksbury, Massachusetts, USA. R.W.G. has financial relationships with

LipoSpectrum and Platomics. P.A.C. serves as a consultant and on a scientific advisory board for Janssen Pharmaceuticals, Titusville, New Jersey, USA. SUPPLEMENTARY INFORMATION SUPPLEMENTARY

TEXT AND FIGURES Supplementary Results, Supplementary Figures 1–12 and Supplementary Tables 1–3. (PDF 13674 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Chen, YJ., Mahieu, N., Huang, X. _et al._ Lactate metabolism is associated with mammalian mitochondria. _Nat Chem Biol_ 12, 937–943 (2016). https://doi.org/10.1038/nchembio.2172

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