Tracing the lactate shuttle to the mitochondrial reticulum

Abstract

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.

A modified formula using energy system contributions to calculate pure maximal rate of lactate accumulation during a maximal sprint cycling test

“…On the other hand, previous researchers suggested no lactate production during t PCr which was incorrectly (fictitiously) assumed ( Heck et al, 2003 ; Hauser et al, 2014 ; Adam et al, 2015 ; Nitzsche et al, 2018 ; Quittmann et al, 2020 ; Quittmann et al, 2021 ). In this regard, it is well known that all three energy systems start to work simultaneously and lactate production occurs independently of O 2 availability such as under anoxic, hypoxic, and normoxic conditions ( Gastin, 2001 ; Philp et al, 2005 ; Brooks, 2018 ; Yang et al, 2020 ; Brooks et al, 2022 ; Yang et al, 2022b ). La − might be accumulated at a relatively low level during the initial seconds of the 15-s ASCT because ATP-PCr is a dominant energy contribution until the achievement of W peak ( Serresse et al, 1988 ; Beneke et al, 2002 ; Park et al, 2021 ).…”

Mitochondria: It is all about energy

“…An essential shuttle exists between muscle lactate produced during movement/exercise (driver) and its transfer to the heart and brain (receivers) that use lactate as an important energy source. Lactate from muscular cells can also be used in the liver, kidneys, lungs, sperm, and many other organs, making lactate an essential energy source, opposite to the common opinion that lactate is a toxic metabolite (Brooks, 2018;Brooks, 2020a;Brooks, 2020b;Brooks et al, 2022). Furthermore, the exchange between astrocytes and neurons is common, where lactate is metabolized and excreted by astrocytes and subsequently actively consumed and oxidized by neurons.…”

“…Besides enabling lactate to become a metabolic substrate, mitochondria have a significant role in lactate shuttling. Lactate shuttling enables the exchange of lactate between producer (driver) cells and so-called consumer (recipient) cells ( Brooks et al, 2022 ). The lactate shuttle is propelled from white fibers (drivers) to red fibers (lactate users) thanks to their high mitochondrial density ( Brooks, 2002 ).…”

“…Mitochondria are of essence here, as the shuttling depends on pH and concentration gradients. These are created by mitochondria in recipient (user) cells ( Brooks, 2018 ; Brooks, 2020a ; Brooks, 2020b ; Brooks et al, 2022 ). Mitochondria contain a collection of proteins bound to the IMM and organic molecules, which electrons pass through in a series of redox reactions.…”

From rags to riches: Lactate ascension as a pivotal metabolite in neuroenergetics

“…Similarly, no mechanism has been offered yet, to explain how the presence of mitochondria switch the glycolytic pathway from 11 to 10 reactions. Glycolysis is a pathway present in every other bodily tissue beside the CNS and multiple studies over the past several decades exhibited mitochondrial utilization of lactate as a substrate of oxphos, while other exhibited the presence of LDH intra-mitochondrially (Brooks, 1985(Brooks, , 1998(Brooks, , 2000(Brooks, , 2002aLarrabee, 1996;Hu and Wilson, 1997;Brooks et al, 1999Brooks et al, , 2022Magistretti et al, 1999;Valenti et al, 2002;Mangia et al, 2003;Pellerin and Magistretti, 2003;de Bari et al, 2004de Bari et al, , 2010Kasischke et al, 2004;Serres et al, 2005;Hashimoto et al, 2006Schurr and Payne, 2007;Passarella et al, 2008;Elustondo et al, 2013;Rogatzki et al, 2015;Hui et al, 2017). Therefore, it is even more bewildering that the majority of recently published general information, both in print and online, continues to completely ignore the data proving that the glycolytic pathway, regardless of the presence of oxygen and/or mitochondria, always produces lactate as its end-product.…”