Aerobic Glycolysis: A DeOxymoron of (Neuro)Biology

Abstract

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.

From rags to riches: Lactate ascension as a pivotal metabolite in neuroenergetics

“…The fact that lactate is the one and only terminal glycolytic product, any prefix assigned to "glycolysis" is, in essence, meaningless. This is especially glaring when the term "aerobic glycolysis" that is in use today means that the pathway ends with lactate as its final product without any oxygen consumption, despite the presence of oxygen (Schurr and Passarella, 2022). Consequently, pyruvate should be considered an intermediate, not different from any other glycolytic intermediate.…”

“…Therefore, it is even more bewildering that the majority of recently published general information, both in print and online, continues to completely ignore the data proving that the glycolytic pathway, regardless of the presence of oxygen and/or mitochondria, always produces lactate as its end-product. The terminology "aerobic" and "anaerobic" glycolysis is meaningless, confusing and should be eliminated (Schurr and Passarella, 2022). Interestingly, as early as 1984 it was suggested to use the term "non-robic" glycolysis instead of the terms "aerobic" and "anaerobic" (Brooks and Fahey, 1984), a suggestion that clearly was not accepted.…”

New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases

“…This overwhelming evidence obtained in recent years that aerobic glycolysis or the Warburg effect is not a specific hallmark of cancer makes this dogma obsolete and ready for the biochemical museum. 51 A more accurate concept is that ATP synthesis via glycolysis and lactate formation and/or mitochondrial OXPHOS is regulated as a response to the microenvironment of both normal cells and cancer cells. 8,15,41 As a consequence, it is reasonable to argue that ATP synthesis via aerobic glycolysis is not a realistic target for systemic anticancer therapy and the lack of success in clinical trials is in line with that.…”

Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma

“…ATP production in HepG2 cells greatly depend on OXPHOS ( Yang et al, 2020 ). OXPHOS may be promoted by an increase in the extracellular L-lactate output from neighbouring glycolytic tumour cells ( Hong et al, 2019 ; Schurr & Passarella, 2022 ) Mitochondrial L-lactate dehydrogenase (mL-LDH) is highly expressed in Hep G2 cell, where pyruvate carrier function is diminished. This suggests that pyruvate metabolism may be not the main driver of OXPHOS activity in Hep G2 cells ( Pizzuto et al, 2012 ).…”