An Organismal Perspective on the Warburg Effect and Models for Proliferation Studies

SIMPLE SUMMARY: Considerable interest in the physiology of proliferation has been generated by human cancers. Cancers often share features with other proliferative cells that are exemplified by the Warburg effect, which involves an altered metabolism with less oxygen uptake and greater lactate secretion. While some of the Warburg effect can be rationalized as production of biosynthetic precursors to fuel proliferation, lactate secretion does not fit this paradigm as it wastes these valuable precursors. In this context, examining proliferation in organisms that are capable of anaerobic pathways other than lactate production can be illuminating. Many animal species, and indeed eukaryotes in general, can carry out other bioenergetic reactions that do not use oxygen. These reactions frequently involve mitochondria and employ such seemingly baroque processes as running the Krebs cycle, the metabolic heart of the cell, backwards. Detailed study of these processes may require development of new animal model systems. For example, colonial marine hydroids frequently exhibit a stage in the life cycle that only undergoes cellular proliferation and never produces gametes. In contrast, traditional animal models such as worms, flies, and mice undergo only limited proliferation before gamete production. The crucial unresolved issues related to the Warburg effect could thus be understood. ABSTRACT: Interest in the physiology of proliferation has been generated by human proliferative diseases, i.e., cancers. A vast literature exists on the Warburg effect, which is characterized by aerobic glycolysis, diminished oxygen uptake, and lactate secretion. While these features could be rationalized via the production of biosynthetic precursors, lactate secretion does not fit this paradigm, as it wastes precursors. Forming lactate from pyruvate allows for reoxidizing cytosolic NADH, which is crucial for continued glycolysis and may allow for maintaining large pools of metabolic intermediates. Alternatively, lactate production may not be adaptive, but rather reflect metabolic constraints. A broader sampling of the physiology of proliferation, particularly in organisms that could reoxidize NADH using other pathways, may be necessary to understand the Warburg effect. The best-studied metazoans (e.g., worms, flies, and mice) may not be suitable, as they undergo limited proliferation before initiating meiosis. In contrast, some metazoans (e.g., colonial marine hydrozoans) exhibit a stage in the life cycle (the polyp stage) that only undergoes mitotic proliferation and never carries out meiosis (the medusa stage performs this). Such organisms are prime candidates for general studies of proliferation in multicellular organisms and could at least complement the short-generation models of modern biology.