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 Lactate is emerging as the "good guy," contrasting its classical "bad guy" position in the now superseded medical literature.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.

Keywords: astrocyte-microglia lactate shuttle (AMLS); astrocyte-neuron lactate shuttle (ANLS); infectious neuroinflammatory disease; lactate; neurodegenerative disease; neuroenergetics; neuropathology; traumatic brain injury (TBI).

Figure 1

Schematic representation of the astrocyte-neuron lactate shuttle model (with permission from Bélanger et al., 2011). Glu, glutamate; Gln, glutamine; GluR, glutamatergic receptor; EAATs, excitatory amino acid transporters; GLUT, glucose transporter; MCTs, monocarboxylate transporters; LDH, lactate dehydrogenase; GS, glutaminase; GLS, glutamine synthetase.

Figure 2

Representation of metabolic pathways of two lactate shuttles within the central nervous system. (1) The astrocyte–neuron lactate shuttle (ANLS; green pathway) operates under normal physiological conditions with astrocytes responding to glutamatergic activation by increasing their rate of glucose utilization and release of lactate in the extracellular space, making the lactate available for neurons to sustain their energy demands. (2) The astrocyte–microglia lactate shuttle (AMLS; red pathway) proposed for tuberculous meningitis (TBM). Astrocytes respond to signaling from Mycobacterium tuberculosis (Mtb)-infected microglia by increasing glucose mobilization, leading to increased extracellular lactate, reflected in increased cerebrospinal fluid (CSF) lactate levels. Lactate used by microglia as an additional energy source for reactive oxygen species (ROS) production aimed at destroying the invading Mtb.