Where is lactate metabolized

These experimental approaches can be also applied to measurements of oxygen consumption in the presence or absence of ADP , proton efflux and membrane potential generation in the future.

By applying the control strength criterion with various non-penetrant inhibitors 19 it can be established whether or not the rate of the above processes mirrors that of l -lactate transport across the mitochondrial membrane. Thus, l -lactate transport can be investigated quantitatively, including the occurrence of hyperbolic kinetics, pH profile, etc.

Moreover, comparison made between the inhibition profiles of pyruvate and l -lactate-dependent mitochondrial processes through the use of compounds that are unable to enter mitochondria allows for a distinction between l -lactate and pyruvate carriers.

Briefly, it has also been shown that externally added l -lactate can enter both normal and cancer prostate cells and in particular, in a carrier-mediated manner, enters their mitochondria, where an l -LDH exists and is located in the inner compartment. The m- l -LDHs have been demonstrated to differ from the cytosolic enzymes that themselves differ from one another. Normal and cancer cells show differences with respect to m- l -LDH protein level and activity, where both the enzyme expression and activity are higher in cancer cells.

In , the existence of monocarboxylate transporter MCT and LDH proteins in mitochondrial reticula of breast cancer cell lines was demonstrated In that case, the expression of both MCTs and l -LDH was measured, and their mitochondrial localization was determined via immunofluorescence, a technique that does not allow for the identification of the submitochondrial localization.

A broader investigation of l -lactate transport and metabolism in cancer cell mitochondria was carried out in human hepatocellular carcinoma Hep G2 cells 21 in which gluconeogenesis takes place Cytosolic and mitochondrial l -LDHs were also found to differ from one another in their saturation kinetics. The occurrence of a carrier-mediated l -lactate transport in these mitochondria has also been shown.

Ultimately, the removal of the oxidation product by carrier-mediated transport and mitochondrial metabolism overcomes any theoretical thermodynamic difficulty which was considered to rule out any l -lactate oxidation in the mitochondria. These findings strongly suggest that a revision of the dogmatic view of glucose metabolism is needed with a special focus on the role of l -lactate and m- l -LDH in gluconeogenesis.

In this regard, cellular l -lactate oxidation, which is necessary for the production of glucose in the Cori cycle, has been traditionally postulated to take place in the cytosol, but is it? Therefore, the dogmatic portrayal of this reaction as bidirectional is misleading and has been accepted to date due to the absence of a possible alternative.

We contend that l -lactate oxidation back to pyruvate does not take place in the cytosol, but rather, it occurs in the mitochondria. Therefore, even if we agree with Lu et al. Of special interest is the fact that pyruvate cannot enter Hep G2-M.

Notice that an impairment of pyruvate transport in cancer cells has been reported by Paradies et al. Therefore, independently of the theoretical unfeasibility of l -lactate oxidation in the cytosol, as was explained above, the classic Cori cycle cannot occur in Hep G2cells. Therefore, we offer a revised Cori cycle Figure 1 , which involves both the mitochondrial carriers that mediate the l -lactate-dependent traffic and the m- l -LDH, which provides pyruvate inside mitochondria. Importantly, the addition of l -lactate to Hep G2-M results in the appearance outside mitochondria of citrate, the fatty acid precursor.

Accordingly, by using high-resolution mass spectrometry, l -lactate uptake into mitochondria of HeLa and H cells was found and proved to result in lipid synthesis; additionally, transmission electron microscopy confirmed that LDH is localized to the mitochondria Figure 1. Cori cycle revisited in Hep G2 cells. Given that pyruvate cannot enter Hep G2-M, as shown in Pizzuto et al.

We believe that the proposed revision of the Cori cycle, necessary for Hep G2 cells, should also be considered in all other types of cells where mitochondrial metabolism of l -lactate is active. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer [GP] declared a shared affiliation, with no collaboration, with one of the authors [SP] to the handling Editor. Dianzani MU. Distribution of lactic acid oxidase in liver and kidney cells of normal rats and rats with fatty degeneration of the liver.

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Whole body hypoxia occurring during cardiac arrest or severe hypovolaemia triggers anaerobic metabolism. Lactate concentrations directly reflect cellular hypoxia. Consequently, during in-hospital cardiac arrest and 1 h after return of spontaneous circulation, lactate concentrations are predictive of survival.

During systemic inflammatory response syndrome SIRS or early sepsis, hyperlactaemia may reflect tissue hypoxia. Early enhancement of oxygen delivery improves outcome. Stable septic patients have elevated oxygen delivery and tissue oxygen levels generally exceed those that trigger anaerobic metabolism. Impaired lactate clearance is usually more significant than increased production. Aerobic lactate production in such patients may be involved in modulation of carbohydrate metabolism under stress.

Gut hypoxia causes anaerobic metabolism. The liver receives more lactate from the portal vein. Initially, this is oxidized or converted to glucose by the periportal hepatocytes. Bacterial translocation and profound fluid shifts contribute to circulatory collapse. Global oxygen delivery falls. Endogenous catecholamine release attempts to support the circulation but will also increase glycolysis and lactate formation.

As shock develops hepatic blood flow falls and intracellular acidosis inhibits gluconeogenesis from lactate. The liver produces rather than clears lactate. Intestinal bacteria metabolize glucose and carbohydrate to d -lactate.

This is only slowly metabolized by human LDH and contributes to the escalating lactic acidosis. Google Scholar. Google Preview. Please see multiple choice questions 28— Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume 6. This article was originally published in. Article Contents Normal lactate production.

Measurement of lactate. Lactate and lactic acidosis.