Tracing the lactate shuttle to the mitochondrial reticulum

• Published in: Experimental & molecular medicine Vol. 54; no. 9; pp. 1332 - 1347
• Main Authors: Brooks, George A., Curl, Casey C., Leija, Robert G., Osmond, Adam D., Duong, Justin J., Arevalo, Jose A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2022; Springer Nature B.V; 생화학분자생물학회
• Subjects: 101/1; 101/58; 13; 14; 14/19; 14/28; 38; 38/1; 59; 631/443/319/333; 692/163/2743/2037; Astrocytes; Biomedical and Life Sciences; Biomedicine; Blood flow; Cardiac muscle; Cytosol; Endoplasmic Reticulum Stress; Energy resources; Fatty Acids - metabolism; Female; Glucose - metabolism; Glycerol; Glycerol - metabolism; Humans; Intracellular; Lactic acid; Lactic Acid - metabolism; Male; Medical Biochemistry; Metabolism; Metabolites; Mitochondria; Mitochondria - metabolism; Molecular Medicine; Muscle, Skeletal - metabolism; Musculoskeletal system; Oxidative metabolism; Peroxisomes; Producer cells; Review; Review Article; Sea level; Skeletal muscle; Stem Cells; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-022-00802-3

Isotope tracer infusion studies employing lactate, glucose, glycerol, and fatty acid isotope tracers were central to the deduction and demonstration of the Lactate Shuttle at the whole-body level. In concert with the ability to perform tissue metabolite concentration measurements, as well as determinations of unidirectional and net metabolite exchanges by means of arterial–venous difference (a-v) and blood flow measurements across tissue beds including skeletal muscle, the heart and the brain, lactate shuttling within organs and tissues was made evident. From an extensive body of work on men and women, resting or exercising, before or after endurance training, at sea level or high altitude, we now know that Organ–Organ, Cell–Cell, and Intracellular Lactate Shuttles operate continuously. By means of lactate shuttling, fuel-energy substrates can be exchanged between producer (driver) cells, such as those in skeletal muscle, and consumer (recipient) cells, such as those in the brain, heart, muscle, liver and kidneys. Within tissues, lactate can be exchanged between white and red fibers within a muscle bed and between astrocytes and neurons in the brain. Within cells, lactate can be exchanged between the cytosol and mitochondria and between the cytosol and peroxisomes. Lactate shuttling between driver and recipient cells depends on concentration gradients created by the mitochondrial respiratory apparatus in recipient cells for oxidative disposal of lactate.
Metabolism: Reviewing the lactate shuttle
Studies using isotope tracer technologies have significantly improved understanding of how lactate, a metabolite produced as fuel during normal metabolism and in response to exercise, moves or ‘shuttles’ throughout the body. George Brooks and colleagues at the University of California, Berkeley, USA, reviewed the history of the understanding of lactate shuttling, which has largely been informed by human studies using isotope tracer infusions during rest and exercise. Such research highlights continuous organ–organ, cell–cell, and intracellular lactate shuttling. Lactate moves between producer cells such as skeletal muscle cells and consumer cells in tissues including the heart and brain, where it is preferred over glucose as an energy source. Shuttling depends on lactate concentration gradients created by mitochondrial networks in recipient cells. Lactate is disposed of via oxidation.