Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology

The term ‘aerobic glycolysis’ has been in use ever since Warburg conducted his research on cancer cells’ proliferation and discovered that cells use glycolysis to produce adenosine triphosphate (ATP) rather than the more efficient oxidative phosphorylation (oxphos) pathway, despite an abundance of oxygen. When measurements of glucose and oxygen utilization by activated neural tissue indicated that glucose was consumed without an accompanied oxygen consumption, the investigators who performed those measurements also termed their discovery ‘aerobic glycolysis’. Red blood cells do not contain mitochondria and, therefore, produce their energy needs via glycolysis alone. Other processes within the central nervous system (CNS) and additional organs and tissues (heart, muscle, and so on), such as ion pumps, are also known to utilize glycolysis only for the production of ATP necessary to support their function. Unfortunately, the phenomenon of ‘aerobic glycolysis’ is an enigma wherever it is encountered, thus several hypotheses have been produced in attempts to explain it; that is, whether it occurs in cancer cells, in activated neural tissue, or during postprandial or exercise metabolism. Here, it is argued that, where the phenomenon in neural tissue is concerned, the prefix ‘aerobic’ in the term ‘aerobic glycolysis’ should be removed. Data collected over the past three decades indicate that L-lactate, the end product of the glycolytic pathway, plays an essential role in brain energy metabolism, justifying the elimination of the prefix ‘aerobic’. Similar justification is probably appropriate for other tissues as well.

Cellular Signaling

Cell communication in the nervous system is finely tuned to respond rapidly to external stimuli, to modify itself according to those stimuli, and to produce more effective responses in the future. The physical basis for this cell communication is the manipulation of ion gradients with ion pumps and channels, chemical neurotransmission, and synaptic plasticity, all of which are discussed in this chapter.

Hypometabolic Responses to Chronic Hypoxia: A Potential Role for Membrane Lipids

Metabolic suppression is an essential strategy to cope with chronic hypoxia. This review examines the physiological processes used to survive in low oxygen environments. It proposes a novel mechanism–the remodeling of membrane lipids–to suppress ATP use and production. Temperature (homeoviscous adaptation), diet (natural doping in migrant birds) and body mass (membrane pacemaker of metabolism) have an impact on the lipid composition of membranes, which, in turn, modulates metabolic capacity. Vertebrate champions of hypoxia tolerance show extensive changes in membrane lipids upon in vivo exposure to low oxygen. These changes and those observed in hibernating mammals can promote the downregulation of ion pumps (major ATP consumers), ion channels, mitochondrial respiration capacity (state 3, proton leak, cytochrome c oxidase), and energy metabolism (β-oxidation and glycolysis). A common membrane signal regulating the joint inhibition of ion pumps and channels could be an exquisite way to preserve the balance between ATP supply and demand in hypometabolic states. Membrane remodeling together with more traditional mechanisms could work in concert to cause metabolic suppression.

Functional Mechanism of Proton Pump-Type Rhodopsins Found in Various Microorganisms as a Potential Effective Tool in Optogenetics

Microbial rhodopsins, which are photoreceptive membrane proteins consisting of seven α-helical structural apoproteins (opsin) and a covalently attached retinal chromophore, are one of the most frequently used optogenetic tools. Since the first success of neuronal activation by channelrhodopsin, various microbial rhodopsins functioning as ion channels or pumps have been applied to optogenetics. The use of light-driven ion pumps to generate large negative membrane potentials allows the silencing of neural activity. Although anion-conductive channelrhodopsins have been recently discovered, light-driven outward H+-pumping rhodopsins, which can generate a larger photoinduced current than a light-driven inward Cl−-pump halorhodopsin, must be more efficient tools for this purpose and have been often utilized for optogenetics. There are abundant proton pumps in the microbial world, providing numerous candidates for potential practical optogenetic instruments. In addition, their distinctive features (that is, being accompanied by photoinduced intracellular pH changes) could enable expansion of this technique to versatile applications. Thus, intensive investigation of the molecular mechanisms of various microbial H+-pumps may be useful for the exploration of more potent tools and the creation of effectively designed mutants. In this chapter, we focus on the functional mechanism of microbial H+-pumping rhodopsins. Further, we describe the future prospects of these rhodopsins for optogenetic applications.

Interactions between Diameter, Myelination and the Na/K pump Affect Axonal Resilience to High Frequency Spiking

Axons reliably conduct action potentials between neurons and/or other targets. Axons have widely variable diameters and can be myelinated or unmyelinated. Although the effect of these factors on propagation speed is well studied, how they constrain axonal resilience to high frequency spiking is incompletely understood. Maximal firing frequencies range from ~ 1 Hz to > 300 Hz across neurons, but the process by which Na/K pumps counteract Na+ influx is slow, and it is unclear the extent to which slow Na+ removal is compatible with high frequency spiking. Modeling the process of Na+ removal in unmyelinated and myelinated axons shows that both increasing diameter and myelination slow down [Na+] accumulation and increase axonal resilience to high frequency spiking. Increasing pump density alleviates [Na+] accumulation, but can paradoxically reduce the resilience. We speculate that [Na+] accumulation may contribute to fatigue after continuous high frequency firing.SignificanceThe reliability of spike propagation in axons is determined by complex interactions between ionic currents, ion pumps and morphological properties. We use compartment-based modeling to uncover that interactions of diameter, myelination and the Na/K pump determine axonal resilience to high frequency spiking. The Na/K pump can play a double-edged sword role in affecting axonal excitability. Our findings suggest that slow sodium removal influences axonal resilience to high frequency spiking, and may also contribute to fatigue.

Physiological Effects of the Electrogenic Current Generated by the Na /K Pump in Mammalian Articular Chondrocytes

Background: Although the chondrocyte is a non-excitable cell, there is strong interest in gaining detailed knowledge of its ion pumps, channels, exchangers and transporters. In combination, these transport mechanisms set the resting potential, regulate cell volume and strongly modulate responses of the chondrocyte to endocrine agents and physicochemical alterations in the surrounding extracellular micro-environment.Materials and Methods: Mathematical modeling was used to assess the functional roles of energy-requiring active transport, the Na+/K+ pump, in chondrocytes.Results: Our findings illustrate plausible physiological roles for the Na+/K+ pump in regulating the resting membrane potential and suggest ways in which specific molecular components of pump can respond to the unique electrochemical environment of the chondrocyte.Conclusion: This analysis provides a basis for linking chondrocyte electrophysiology to metabolism and yields insights into novel ways of manipulating or regulating responsiveness to external stimuli both under baseline conditions and in chronic diseases such as osteoarthritis (OA).

Structure and Mechanism of P-Type ATPase Ion Pumps

P-type ATPases are found in all kingdoms of life and constitute a wide range of cation transporters, primarily for H+, Na+, K+, Ca2+, and transition metal ions such as Cu(I), Zn(II), and Cd(II). They have been studied through a wide range of techniques, and research has gained very significant insight on their transport mechanism and regulation. Here, we review the structure, function, and dynamics of P2-ATPases including Ca2+-ATPases and Na,K-ATPase. We highlight mechanisms of functional transitions that are associated with ion exchange on either side of the membrane and how the functional cycle is regulated by interaction partners, autoregulatory domains, and off-cycle states. Finally, we discuss future perspectives based on emerging techniques and insights.