Article,
Determinants of Brain Cell Metabolic Phenotypes and Energy Substrate Utilization Unraveled with a Modeling Approach
PLoS Comput Biol, 8 (9): e1002686+ (Sep 13, 2012)
DOI: 10.1371/journal.pcbi.1002686
Abstract
Although all brain cells bear in principle a comparable potential in terms of energetics, in reality they exhibit different metabolic profiles. The specific biochemical characteristics explaining such disparities and their relative importance are largely unknown. Using a modeling approach, we show that modifying the kinetic parameters of pyruvate dehydrogenase and mitochondrial NADH shuttling within a realistic interval can yield a striking switch in lactate flux direction. In this context, cells having essentially an oxidative profile exhibit pronounced extracellular lactate uptake and consumption. However, they can be turned into cells with prominent aerobic glycolysis by selectively reducing the aforementioned parameters. In the case of primarily oxidative cells, we also examined the role of glycolysis and lactate transport in providing pyruvate to mitochondria in order to sustain oxidative phosphorylation. The results show that changes in lactate transport capacity and extracellular lactate concentration within the range described experimentally can sustain enhanced oxidative metabolism upon activation. Such a demonstration provides key elements to understand why certain brain cell types constitutively adopt a particular metabolic profile and how specific features can be altered under different physiological and pathological conditions in order to face evolving energy demands. In an environment with appropriate oxygen levels (normoxia), most eukaryotic cells produce energy by oxidizing glucose into carbon dioxide and water. In this process, glucose is transformed into pyruvate, which then fuels oxidative phosphorylation in the mitochondria. Interestingly, Otto Warburg reported back in the 1920's that some eukaryotic cells prominently process glucose-derived pyruvate into lactate, hence ” avoiding" the mitochondrial oxidation despite adequate oxygen concentrations. This phenomenon was termed aerobic glycolysis and was first observed in cancer cells. Since then, it has also been described in several normal tissues including the central nervous system. The biochemical basis of aerobic glycolysis has remained elusive until now. Taking advantage of a modeling approach, we unraveled the main metabolic characteristics that determine whether a cell will be strictly oxidative or rather will exhibit aerobic glycolysis. When applied in the context of the central nervous system, our findings not only provide a theoretical demonstration of why neurons and astrocytes differ in terms of metabolic profile, but also suggest that such complementarity forms the basis for metabolic cooperation between the two cell types.
