Mitochondrion 17 (2014) 76–100 Contents lists available at ScienceDirect Mitochondrion journal homepage: www.elsevier.com/locate/mito Review Comprehensive review on lactate metabolism in human health☆,☆☆ M. Adeva-Andany a,⁎, M. López-Ojén b, R. Funcasta-Calderón a,1,E.Ameneiros-Rodrígueza,1, C. Donapetry-García a,1, M. Vila-Altesor a,1, J. Rodríguez-Seijas a,1 a Nephrology Division, Hospital General Juan Cardona, Ave. Pardo Bazán, s/n, 15406 Ferrol, La Coruña, Spain b Internal Medicine Division, Policlínica Assistens, c/Federico García, 4-planta baja, 15009 La Coruña, Spain article info abstract Article history: Metabolic pathways involved in lactate metabolism are important to understand the physiological response to Received 18 October 2013 exercise and the pathogenesis of prevalent diseases such as diabetes and cancer. Monocarboxylate transporters Received in revised form 19 March 2014 are being investigated as potential targets for diagnosis and therapy of these and other disorders. Glucose and al- Accepted 5 May 2014 anine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen Available online 12 June 2014 consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. Pyruvate may be either oxidized to carbon dioxide producing energy or transformed into glucose. Pyruvate oxidation requires Keywords: Glycolysis oxygen supply and the cooperation of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondri- Tricarboxylic acid cycle al respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. Con- Respiratory chain genital or acquired deficiency on gluconeogenesis or pyruvate oxidation, including tissue hypoxia, may induce Gluconeogenesis lactate accumulation. Both obese individuals and patients with diabetes show elevated plasma lactate concentra- Insulin resistance tion compared to healthy subjects, but there is no conclusive evidence of hyperlactatemia causing insulin resis- Diabetes mellitus tance. Available evidence suggests an association between defective mitochondrial oxidative capacity in the pancreatic β-cells and diminished insulin secretion that may trigger the development of diabetes in patients al- ready affected with insulin resistance. Several mutations in the mitochondrial DNA are associated with diabetes mellitus, although the pathogenesis remains unsettled. Mitochondrial DNA mutations have been detected in a number of human cancers. D-lactate is a lactate enantiomer normally formed during glycolysis. Excess D-lactate is generated in diabetes, particularly during diabetic ketoacidosis. D-lactic acidosis is typically associated with small bowel resection. © 2014 Elsevier B.V. and Mitochondria Research Society. All rights reserved. Contents 1. Introduction...............................................................78 2. L-lactatemetabolism...........................................................78 2.1. Metabolic pathways involved in L-lactateformation..........................................78 2.1.1. L-lactateformationfromalanine..............................................78 2.1.2. L-lactateformationfromglucose..............................................78 2.2. Metabolic pathways involved in L-lactateclearance..........................................79 2.2.1. Oxidativemetabolismofpyruvate.............................................79 2.2.2. Thegluconeogenesispathway...............................................80 3. D-lactatemetabolism...........................................................80 Abbreviations: ADP, adenosine diphosphate; ALT, alanine aminotransferase; ATP, adenine triphosphate; CoA, coenzyme A; FAD, flavin adenine dinucleotide; FADH2, reduced flavin adenine dinucleotide; GPT, glutamate pyruvate transaminase; HIV, human immunodeficiency virus; LDH, lactate dehydrogenase; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke- like episodes syndrome; MCT, proton-coupled monocarboxylate transporter; MIDD, maternally inherited diabetes mellitus and deafness; NAD+, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NRTI, nucleoside analogs reverse transcriptase inhibitors; PDH, pyruvate dehydrogenase; PEPCK, phosphoenolpyruvate carboxykinase; SMCT, sodium-linked monocarboxylate transporter; TCA, tricarboxylic acid; T2D, type 2 diabetes mellitus. ☆ There was no financial support for this work. ☆☆ The authors declare that they have no conflict of interest. ⁎ Corresponding author. Tel.: +34 664 527 257, +34 981 31 25 00. E-mail address: [email protected] (M. Adeva-Andany). 1 Tel.: +34 981 31 25 00. http://dx.doi.org/10.1016/j.mito.2014.05.007 1567-7249/© 2014 Elsevier B.V. and Mitochondria Research Society. All rights reserved. M. Adeva-Andany et al. / Mitochondrion 17 (2014) 76–100 77 4. Lactatetransportacrossplasmamembranesinthehumanbody....................................... 80 4.1. Proton-coupledmonocarboxylatetransporters(MCTs)........................................ 80 4.1.1. Substratesandtransportmechanismofproton-linkedmonocarboxylatetransporters...................... 80 4.1.2. Humangenesencodingproton-linkedmonocarboxylatetransporters............................. 81 4.1.3. Humantissueexpressionofproton-linkedmonocarboxylatetransporters........................... 81 4.1.4. Regulationofproton-coupledmonocarboxylatetransporters................................. 81 4.1.5. Potentialroleofproton-coupledmonocarboxylatetransportersonhumancancer........................ 81 4.2. Sodium-coupledmonocarboxylatetransporters........................................... 81 4.2.1. SMCT1(SLC5A8)..................................................... 81 4.2.2. SMCT2(SLC5A12).................................................... 82 5. Lactatehandlingbydifferenthumantissues................................................ 82 5.1. Lactatehandlingbyskeletalmuscle................................................. 82 5.1.1. Restingskeletalmuscle.................................................. 82 5.1.2. Activeskeletalmuscle................................................... 82 5.1.3. Physiologicalresponsetoexercise-inducedhyperlactatemia................................. 82 5.1.4. Effectoftrainingonskeletalmusclelactateproductionandtransport............................. 82 5.1.5. Lactateproductionbyskeletalmuscleandoxygendelivery.................................. 82 5.2. Lactatehandlingbythehumanheart................................................ 83 5.3. Lactatehandlingbythehumanbrain................................................ 83 5.4. Lactatehandlingbythehumanliver................................................ 83 5.5. Lactatehandlingbythehumankidney............................................... 84 5.6. Lactatehandlingbythehumanadiposetissue............................................ 84 5.7. Lactatehandlingbythehumanlung................................................ 84 5.8. Lactatehandlingbyhumanbloodcells............................................... 84 6. Interorgan flowoflactate......................................................... 84 7. Insulinresistanceandlactatemetabolisminhumans............................................ 85 7.1. Glucosemetabolismandlactateformationinhealthyhumans..................................... 85 7.1.1. Lactatemetabolisminresponsetoglucoseorinsulinchallenge................................ 85 7.1.2. Tissuesresponsibleforthehyperlactatemiaassociatedwithglucoseorinsulinchallenge.....................85 7.2. Obesityandlactatemetabolisminhumans............................................. 86 7.2.1. Glucosemetabolisminobesityandlactateformation..................................... 86 7.2.2. Fastingplasmalactateconcentrationinobesity....................................... 86 7.2.3. Lactatemetabolisminresponsetoglucoseorinsulinchallengeinobesity............................86 7.2.4. Tissuesresponsibleforobesity-associatedhyperlactatemia.................................. 86 7.3. Diabetesmellitusandlactatemetabolisminhumans......................................... 87 7.3.1. Glucosemetabolismindiabetesandlactateformation.................................... 87 7.3.2. Fastingplasmalactateconcentrationindiabetesmellitus................................... 87 7.3.3. Lactatemetabolisminresponsetoglucoseorinsulinchallengeindiabetesmellitus....................... 87 7.3.4. Tissuesresponsiblefordiabetes-associatedhyperlactatemia................................. 87 7.3.5. Roleofthemitochondrialdysfunctioninthediabetes-associatedhyperlactatemia........................88 7.3.6. DiabetescausedbymitochondrialDNAmutations...................................... 89 8. Causes of L-lacticacidosis......................................................... 89 8.1. Pyruvatetransportinsidethemitochondrialnetwork......................................... 90 8.2. Pyruvate dehydrogenase complex deficiency............................................. 90 8.3. Tricarboxylicacidcycledysfunction................................................. 90 8.4. Congenitalmitochondrialrespiratorychaindysfunction........................................ 90 8.5. Acquiredmitochondrialrespiratorychaindysfunction........................................ 90 8.5.1. Carbonmonoxidepoisoning................................................ 90 8.5.2. Cyanidepoisoning.................................................... 91 8.5.3. Drugs.........................................................