Lactate Shuttles in Neuroenergetics—Homeostasis, Allostasis and Beyond

Abstract

Understanding brain energy metabolism—neuroenergetics—is becoming increasingly important as it can be identified repeatedly as the source of neurological perturbations. Within the scientific community we are seeing a shift in paradigms from the traditional neurocentric view to that of a more dynamic, integrated one where astrocytes are no longer considered as being just supportive, and activated microglia have a profound influence. Lactate is emerging as the “good guy,” contrasting its classical “bad guy” position in the now superseded medical literature. This review begins with the evolution of the concept of “lactate shuttles”; goes on to the recent shift in ideas regarding normal neuroenergetics (homeostasis)—specifically, the astrocyte–neuron lactate shuttle; and progresses to covering the metabolic implications whereby homeostasis is lost—a state of allostasis, and the function of microglia. The role of lactate, as a substrate and shuttle, is reviewed in light of allostatic stress, and beyond—in an acute state of allostatic stress in terms of physical brain trauma, and reflected upon with respect to persistent stress as allostatic overload—neurodegenerative diseases. Finally, the recently proposed astrocyte–microglia lactate shuttle is discussed in terms of chronic neuroinflammatory infectious diseases, using tuberculous meningitis as an example. The novelty extended by this review is that the directionality of lactate, as shuttles in the brain, in neuropathophysiological states is emerging as crucial in neuroenergetics.

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

“…It has also recently been noted in cancer biochemistry that lactate production and release extracellularly may provide a cell non-autonomous bioenergetic resource supportive of high metabolic activity and biosynthesis (San-Millan & Brooks, 2017). Such a system has been described in the brain (i.e., the neuron/ astrocyte lactate shuttle), although its role in AD remains understudied (Mason, 2017;Newington, Harris, & Cumming, 2013).…”

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…Although history did not give lactate its due importance, it is believed at presentthat lactate has a crucial role, especially as a shuttle molecule. The concept was introduced by Brooks more than 30 years ago (7)(8)(9), and despite some initial disbelief (10,11), several reports have finally acknowledged the role of lactate in shuttles between glycolytic and oxidative cells, being the product of one and used by another (12). It is well-established that lactate is formed from the reduction of pyruvate via lactate dehydrogenase (LDHA), under aerobic or anaerobic conditions, produced, and transformed continuously by resting/exercising muscle, brain, heart, and gut tissues (13).…”

“…Lactate is a major source of energy, the major gluconeogenic precursor and, as a signaling molecule, is capable of inducing autocrine, paracrine, and endocrine-like effects. This molecule is responsible for several homeostatic functions: For instance, in hepatocytes, it feeds gluconeogenesis; in the brain, it is used by astrocytes and neurons for oxidative metabolism (12,14).…”

Lactate supplementation in severe traumatic brain injured adults by primed constant infusion of sodium L‐lactate

“…In the attempt to provide alternative fuels to the brain, monitoring systemic changes is important to consider because of the pivotal role lactate plays in systemic signaling (Leverve, 2001; Mosienko et al, 2015; Proia et al, 2016; Mason, 2017). One limitation of our blood plasma metabolite analysis is that we were only able to report on 9 metabolites due to sensitivity limitations of NMR spectroscopy and limited blood plasma for NMR analysis.…”