Research Topic

Glycolysis Paradigm Shift Calls for Reevaluation of Functional Brain Imaging and Pathology Analyses

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Our knowledge and understanding of energy metabolism in general and of glycolysis, in particular, have seen much progress over the past five decades. Among the more significant discoveries in this field of research is the demonstration that the glycolytic pathway in most, if not all, tissues ends up with ...

Our knowledge and understanding of energy metabolism in general and of glycolysis, in particular, have seen much progress over the past five decades. Among the more significant discoveries in this field of research is the demonstration that the glycolytic pathway in most, if not all, tissues ends up with lactate as its final product. This contradicts the prevailing dogma according to which the glycolytic pathway has two potential outcomes, aerobic, where the end-product is pyruvate, and anaerobic, where the end-product is lactate. ¨

Nevertheless, disagreements still exist as to the meaning of this discovery and its importance and there are some who still question its validity. The lasting academic ramifications of this controversy impact the teaching of the subject at all levels, from middle school through medical school. Additionally, there are concerns about the interpretation, understanding and treatment of energy metabolic disorders where brain functional imaging and measurements of cerebral metabolic rates of glucose (CMRglucose) and oxygen (CMRO2) are performed. Measurement of CMRglucose and CMRO2 in two exemplary publications, one by Fox et al. (Science, 241, 462-464, 1988) and the other by Hyder et al. (J. Cereb. Blood Flow Metab. 17, 1040-1047, 1997) best illustrate these concerns. The former study concluded that the energy needs of activated neural tissue is not significantly higher than those of the resting brain tissue and can be met by "aerobic glycolysis" alone (i.e., glycolysis uncoupled from oxygen consumption despite the presence of ample oxygen concentration in the tissue; glucose + 2ATP → lactate + 4ATP). The latter study concluded that activated neural tissue meets its energy needs via a fully aerobic consumption of glucose (i.e., glycolysis coupled to mitochondrial respiration; glucose + 2ATP + 6O2 → 6CO2 + 6H2O + 36ATP). Could the postulated paradigm shift in glycolysis resolve the conflicting conclusions of the two studies as to how activated neural tissue energy needs are being satisfied? Will a measurement of CMRlactate provide a different insight into the means by which neural tissue generates the energy necessary to maintain its activity upon stimulation? The established ability of brain tissue to oxidize lactate to pyruvate via a mitochondrial lactate dehydrogenase (mLDH) points to the possibility that the former plays a major role in sustaining this tissue's activity when both glucose and ATP levels are limited. This is especially plausible since lactate as a mitochondrial substrate of the tricarboxylic acid (TCA) cycle, unlike glucose, does not require an investment of ATP prior to the yield of 17 moles of ATP for each mole of lactate oxidized. Could CMRlactate measurement in diseases involving cognitive decline, associated with brain disorders such as cerebral ischemia, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ASL), Alzheimer's disease, epilepsy, or other metabolic diseases help elucidating their mechanism?

The proposed Research Topic seeks contributions by experts in the fields of energy metabolism, functional brain imaging and brain metabolic disorders that consider the proposed glycolysis paradigm shift with the aim of generating a productive scientific discussion. All contributions, whether in the form of original research article, review, opinion or perspective are welcomed.


Keywords: Cerebral Metabolic Rates, Glucose, Lactate, NAD+/NADH, Oxygen


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21 August 2019 Manuscript

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21 August 2019 Manuscript

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