Full-length reviewCNS energy metabolism as related to function
Introduction
At times of peak activity, some regions in the CNS use as much energy as any other tissue in the body, including striated muscle (see below). Understanding the energy metabolism of neurons and associated glial cells is of importance for understanding the normal function of brain, and for understanding a variety of pathological states.
Energy metabolism was one of the earliest studied aspects of brain biochemistry, and a large body of information has been accumulated. Prominent publications include the classic studies from Lowry’s laboratory [127], the extensive review by Siesjo [204], and more recent reviews by Erecinska and Silver [63], [65].
Our understanding of brain energy metabolism continues to evolve; and some of the more recent studies, not all of them on brain itself, have provided information about the energy metabolism of cells that has required a considerable modification of our previous views. A number of these more recent revelations are the subjects of this review: (1) it is now clear that energy metabolism is highly organized within cells, and that special mechanisms have evolved to transfer energy efficiently from the site of generation to the site of consumption. As a consequence, there is heterogeneity between one part of a cell and another with respect to energy metabolism. (2) It has also become clear that glycolysis (glucose→lactate) plays an important role in some regions of the normally oxygenated brain and in some parts of cells, with the lactate generated at one site serving as substrate for oxidative metabolism at another. (3) The relative importance of glycolytic versus oxidative metabolism differs markedly between cell types, and symbiotic arrangements appear to have evolved between glia and neurons. (4) More is now known about why the brain requires so much energy, and it has become possible to make preliminary estimates of the various demands on the cells’ energy supplies. (5) Comparisons between the capacity of cells to generate energy and their requirements for energy at times of maximal activity have raised the possibility of temporary energy imbalances under normal conditions. (6) Evidence has been obtained for mechanisms that reduce activity and preserve ATP at times of energy limitations.
This review addresses problems for which we do not yet have answers or have only speculative answers. No attempt has been made to review the chemical reactions that generate energy or to review research concerning the critical control points in the glycolytic and oxidative sequences. Much of the discussion assumes that energy generation is linked quite directly to energy consumption; i.e., that reductions in ATP and increases in ADP, AMP, and Pi are the principal controlling factors in both glycolytic and oxidative metabolism (see Ref. [62] and Refs. therein). The important problem of how regional blood flow (rCBF) is altered in response to changes in energy requirements is not discussed. See, for example, reviews by Brian et al. [31] and Harder et al. [84].
Since the mechanisms used to deliver energy to the processes that require it have been difficult to examine in the brain in situ (largely because of its inaccessibility and fine-grained heterogeneity, see below), this review cites studies on in vitro preparations of CNS including cultured cells, and also cites studies on tissues other than brain (e.g., muscle). I believe this to be warranted since energy transfer is such a fundamental requirement of all cell types that the mechanisms utilized can be expected to be quite general. It should, however, be recognized that final conclusions must await the development of techniques applicable to the in vivo brain.
Section snippets
Experimental obstacles
Our continuing ignorance about many aspects of brain energy metabolism can be attributed to the difficulties inherent in devising revealing experiments. Physical access to the brain is restricted by the skull. Chemical access is restricted by the blood–brain barrier. Energy-related reactions proceed so rapidly that efficient quenching is required to harvest specimens that reflect the conditions that pertain in vivo. But the greatest difficulties facing the investigator are the problems of
Organization of energy metabolism within cells
Providing ∼P at appropriate rates to energy-consuming enzymes throughout the cell requires not only organized systems for generating the ∼P but also organized means of delivery. The concept, once held, of a single intracellular pool of ATP — supplied by glycolytic and oxidative reactions, and drawn upon by various ATPases depending on their Km values — is now recognized as no longer tenable. [‘ATPase’ describes any enzyme that requires the energy in the γ phosphate bond of ATP for its
The role of lactate in brain energy metabolism
Because the principal energy substrates entering the brain are glucose and O2, and the principal products leaving are CO2 and H2O, it was conventionally assumed that brain cells generated virtually all of their ∼P from the direct oxidation of glucose. It now appears that a (still undetermined but probably) substantial portion of the brain’s energy comes from the conversion of glucose to lactate at one site (yielding two ∼P per glucose molecule) and from the oxidation of the lactate at another
What is the energy used for?
Surprisingly little is presently known about the relative magnitude of the various energy demands on CNS cells. It seems reasonable to distinguish conceptually between the energy used for basic vegetative processes (e.g., protein synthesis), and the energy used for processes that underlie specialized physiological functions (e.g., neurotransmission and action potentials).
When energy demands exceed energy generation
If the capacity of CNS cells to generate energy is terminated abruptly (e.g., by circulatory arrest), cell function is lost following a brief latency, the duration of which reflects the level of energy reserves. If, on the other hand, the cells’ capacity to generate energy is only marginally reduced (e.g., in climbers at high altitudes), function may or may not be impaired, depending on the margin of safety that exists between the amount of energy the cells can normally generate and the amount
Summary
- 1.
The energy metabolism of the brain is proving to be considerably more complex than previously realized. Our understanding is still far from complete, and much of it is inferential because techniques have yet to be developed for measuring the rates of reactions as they occur in situ and for measuring them with spatial resolution at the cellular level and with temporal resolution in seconds.
- 2.
Energy metabolism is organized to link energy generation to energy consumption within the cell. ∼P is often
Acknowledgements
The author is grateful to Richard Masland for suggesting he undertake this review in the first place, to Kathleen Sweadner for thoughtful criticism, and to Nora Wilson and Kate Harmon for skilled assistance in preparation of the manuscript.
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