br Conclusion The mitochondrial and glycolytic energy metabo

Conclusion The mitochondrial and glycolytic energy metabolism of the brain is coordinated by HKI binding to MOM, although the molecular mechanism of such a regulation is not yet clear. The DHEA receptor for HKI in MOM are VDACs [[5], [6], [7]], mainly the VDAC1 isoform [8]. Using a computational model, we demonstrated a high probability of the generation of positive OMP by the ANT-VDAC1-HKI mechanism that seems to be prevalent for the brain mitochondria. It is very important that both HKI and VDAC1 have been considered in the last decade as key points in many neurodegenerative disorders [30,[36], [37], [38], [39]]. On the other hand, enhanced resistance to death of some neuronal cells in Alzheimer's disease is due to a development of the Warburg type metabolism [38,50,51], similar to that in cancer cells. As cell death in Alzheimer's disease is strongly related to high level of cytosolic Ca2+, increasing with age [62], the suggested mechanism of metabolically-dependent steady-state generation of positive OMP might protect neuronal cells against Ca2+-activated mitochondrial permeability transition and cell death, like that suggested earlier for cancer cells [42,43] and cardiomyocytes [25]. Moreover, positive OMP of even low magnitudes, not high enough to electrically close free, unbound VDACs in MOM, might modulate ATP4− flux from MIMS into the cytosol, as well as decrease Km,ADP for mitochondrial respiration [25]. In general, the proposed mechanism of OMP generation might be involved in regulation of brain energy metabolism and in various neurodegenerative disorders.
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Main Text The ability to detect and respond to pathogens is essential for an organism’s survival, and one of the first lines of defense against infection is the innate immune system. Metabolic adaptations are at the nexus of innate immune responses. Reprogramming of cellular metabolism in innate immune cells is necessary for their efficient activation, and many antimicrobial defenses such as nitric oxide (NO), reactive oxygen species (ROS), and itaconate are products of metabolic processes (O’Neill and Pearce, 2016). Adding to the diverse role that metabolism has in innate immunity, new research by Wolf et al. (2016) demonstrates that the glycolytic enzyme hexokinase senses Gram-positive bacteria and facilitates inflammasome activation. Mitochondria are key in the induction of the NLRP3 inflammasome, and the work of Wolf et al. (2016) provides an intriguing link between mitochondria and NLRP3 activation. They demonstrate in lipopolysaccharide (LPS)-primed bone marrow-derived macrophages that hexokinase responds to elevated concentrations of N-acetylglucosamine (NAG), a sugar subunit found in bacterial peptidoglycan (PGN), by dissociating from mitochondrial voltage-dependent anion channels (VDACs). Although NAG can both inhibit hexokinase activity, as well as cause its dissociation from VDAC, the induction of the NLRP3 inflammasome appears to be mediated by the latter. Using a peptide that competes with hexokinase for the binding site of VDAC, they find that dissociation of hexokinase from VDAC induces IL-1β and IL-18 production in an NLRP3-dependent manner. Using excess glucose-6-phosphate (hexokinase’s enzymatic product) or the glucose analog 2-deoxyglucose (2-DG), Wolf et al. (2016) also demonstrate that induction of IL-1β occurs following inhibition of hexokinase. To assess these effects in vivo, Wolf et al. (2016) utilized PGN from bacillus anthracis, which contains deacetylated NAG and does not activate the NLRP3 inflammasome. When they re-acetylated the b. anthracis PGN, thus enhancing NAG concentration, an IL-1β dependent inflammatory response was induced. Collectively, their results suggest that NAG induces NLRP3 inflammasome activation through binding and dissociating hexokinase (Figure 1). The signal connecting hexokinase dissociation from VDAC and activation of the NLRP3 inflammasome remains to be determined. Potassium efflux is a common mechanism underlying NLRP3 inflammasome activation (Muñoz-Planillo et al., 2013), but surprisingly it does not appear to play a role in PGN-induced inflammasome activation, as increasing extracellular potassium had no effect on IL-1β production. Also NLRP3 inflammasome activation was not due to loss of mitochondrial integrity, as mitochondrial membrane potential was maintained following PGN administration. Interestingly, this effect is distinct from a previous study that found 2-DG reduced mitochondrial membrane potential in macrophages (Nomura et al., 2015). Another mechanism could be mitochondrial DNA (mtDNA) release, as increased mtDNA was evident in the cytosol in response to PGN. Other inflammasome activators, including mitochondrial ROS and cardiolipin, may also contribute to these effects (Sutterwala et al., 2014).