Presented by Connor Jankowski
Lactate metabolism is associated with mammalian mitochondria. Chen et al., Nature Chemical Biology, Sep. 2016
An Intracellular Fate for Lactate
In this study, Chen. et al show that fermenting HeLa and H460 cells are able to use exogenous lactate for non-gluconeogenic purposes. Using solid-state NMR, isotopic tracing via GC/LC-MS, and transmission electron microscopy, they demonstrate that these cells use lactate carbon to synthesize lipids following mitochondrial oxidation to pyruvate and a subsequently truncated TCA cycle. They propose that this newfound link between lactate metabolism and the mitochondria of fermenting mammalian cells may be a promising future cancer therapy.
Lactate is used to synthesize lipids
Solid-state NMR showed a dramatic increase in peaks associated with lipid aliphatic carbons by 13C NMR. They showed that labeled lipids represented up to 50% of the total label; labeled lipids accounted for about 10% of the total lipid pool and intracellular isotopic enrichment of lactate decreased to 24% within 10 minutes, showing considerable efficiency for its metabolism.
Isolated mitochondria metabolize lactate
13C labeling and subsequent GC/LC-MS analysis of cultured mitochondria isolated from these cell lines showed that carbon originating from lactate enters the TCA cycle and labels citrate but that this isotopic labeling pattern drops off sharply at subsequent steps. These results are consistent with labeled citrate being subsequently used to synthesize lipids, as would be suggested by the NMR spectra. They then show, using a 2H label for lactate, that lactate enters the mitochondria before being oxidized to pyruvate. Finally, they use transmission electron microscopy and ELISA to characterize LDH-B as the mitochondrial form of the enzyme that catalyzes this reaction.
Mitochondria use lactate as a carbon source to respire
Chen et al.’s final study monitored the respiration rate of HeLa and H460 cells under lactate/malate, pyruvate/malate, and LDH-inhibitor conditions. They found that the respiration rate of cells cultured in lactate/malate conditions was dramatically diminished when treated with the LDH-inhibitor oxamate, but that inhibitor had no respiratory effect when lactate in the media was replaced with pyruvate.
The authors conclude by suggesting that these pathways might be used to carry glycolytic reducing agents to the mitochondria and/or to regulate energy metabolism in rapidly dividing cancer cells. They conclude by offering the idea that selective inhibition of mitochondrial LDH-B may be a selective and effective cancer therapeutic.