Glucose In Mitochondria Research Articles

Modelling of energy-driven switch for glucagon and insulin secretion

We present a mathematical model of the energy-driven metabolic switch for glucagon and insulin secretion from pancreatic alpha and beta cells, respectively. The energy status related to hormone secretion is studied for various glucose concentrations. Additionally, the physiological response is studied with regards to the presence of other metabolites, particularly the free-fatty acids. At low glucose, the ATP production in alpha cells is high due to free-fatty acids oxidation in mitochondria, which enables glucagon secretion. When the glucose concentration is elevated above the threshold value, the glucagon secretion is switched off due to the contribution of glycolytic ATP production, representing an “anaerobic switch”. On the other hand, during hypoglycemia, the ATP production in beta cells is low, reflecting a “waiting state” for glucose as the main metabolite. When glucose is elevated above the threshold value, the oxidative fate of glucose in mitochondria is the main source of energy required for effective insulin secretion, i.e. the “aerobic switch”. Our results show the importance of well-regulated and fine-tuned energetic processes in pancreatic alpha and beta cells required for efficient hormone secretion and hence effective blood glucose regulation. These energetic processes have to be appropriately switched on and off based on the sensing of different metabolites by alpha and beta cells. Our computational results indicate that disturbances in cell energetics (e.g. mitochondrial dysfunction), and dysfunctional metabolite sensing and distribution throughout the cell might be related to pathologies such as metabolic syndrome and diabetes.

Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells

Despite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood. Here we show that the glycolytic enzyme pyruvate kinase M2 (PKM2) limits glucose oxidation, and maintains the growth and epigenetic state of ECs. We find that loss of PKM2 alters mitochondrial substrate utilization and impairs EC proliferation and migration in vivo. Mechanistically, we show that the NF-κB transcription factor RELB is responsive to PKM2 loss, limiting EC growth through the regulation of P53. Furthermore, S-adenosylmethionine synthesis is impaired in the absence of PKM2, resulting in DNA hypomethylation, de-repression of endogenous retroviral elements (ERVs) and activation of antiviral innate immune signalling. This work reveals the metabolic and functional consequences of glucose oxidation in the endothelium, highlights the importance of PKM2 for endothelial growth and links metabolic dysfunction with autoimmune activation in ECs.

Oligodendrocytes: Development, Physiology and Glucose Metabolism.

The glutamate-glutamine cycle is an outstanding example of how essential neuronal-glial interactions are for brain function. For several decades, this and other metabolic cycles in the brain have only included neurons and astrocytes but not oligodendrocytes, the myelinating cells of the central nervous system (CNS). Recent data revealed that oligodendrocytes are highly metabolically active cells in the brain and, therefore, should not be ignored. Using 13C-labelled glucose in combination with nuclear magnetic resonance spectroscopy (MRS) and/or mass spectrometry (MS) it is possible to characterize metabolic functions in primary oligodendrocyte cultures. Mature rat oligodendrocytes avidly metabolize glucose in the cytosol and pyruvate derived from glucose in mitochondria. Moreover, they seem to have the ability of performing anaplerosis from pyruvate, which might enable them to synthesize metabolites de novo and transfer them to neighbouring cells. All these original findings highlight the importance of investigating oligodendrocyte metabolism separately from that of astrocytes and neurons to be able to discern the roles played by the individual partners. This is of particular importance in the white matter where the number of oligodendrocytes is considerable. The present book chapter provides some background on oligodendrocyte biology and physiology and summarizes the not very extensive information published on glucose metabolism in oligodendrocytes.