Lactate metabolism is associated with mammalian mitochondria

Ying Jr Chen; Nathaniel G. Mahieu; Xiaojing Huang; Manmilan Singh; Peter A. Crawford; Stephen L. Johnson; Richard W. Gross; Jacob Schaefer; Gary J. Patti

doi:10.1038/nchembio.2172

Lactate metabolism is associated with mammalian mitochondria

Ying Jr Chen, Nathaniel G. Mahieu, Xiaojing Huang, Manmilan Singh, Peter A. Crawford, Stephen L. Johnson, Richard W. Gross, Jacob Schaefer, Gary J. Patti

Molecular Medicine

Research output: Contribution to journal › Article › peer-review

167 Scopus citations

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.

Original language	English (US)
Pages (from-to)	937-943
Number of pages	7
Journal	Nature Chemical Biology
Volume	12
Issue number	11
DOIs	https://doi.org/10.1038/nchembio.2172
State	Published - Nov 1 2016

Bibliographical note

Funding Information:
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.

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© 2016 Nature America, Inc. All rights reserved.

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title = "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.",

author = "Chen, {Ying Jr} and Mahieu, {Nathaniel G.} and Xiaojing Huang and Manmilan Singh and Crawford, {Peter A.} and Johnson, {Stephen L.} and Gross, {Richard W.} and Jacob Schaefer and Patti, {Gary J.}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",

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AU - Johnson, Stephen L.

AU - Gross, Richard W.

AU - Schaefer, Jacob

AU - Patti, Gary J.

N1 - Funding Information: 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. Publisher Copyright: © 2016 Nature America, Inc. All rights reserved.

PY - 2016/11/1

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N2 - 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.

AB - 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.

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Lactate metabolism is associated with mammalian mitochondria

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