The mitochondrial calcium uniporter, which regulates aerobic metabolism by catalyzing mitochondrial Ca2+ influx, is arguably the most selective ion channel known. The mechanisms for this exquisite Ca2 Show more
The mitochondrial calcium uniporter, which regulates aerobic metabolism by catalyzing mitochondrial Ca2+ influx, is arguably the most selective ion channel known. The mechanisms for this exquisite Ca2+ selectivity have not been defined. Here, using a reconstituted system, we study the electrical properties of the channel's minimal Ca2+-conducting complex, MCU-EMRE, from Tribolium castaneum to probe ion selectivity mechanisms. The wild-type TcMCU-EMRE complex recapitulates hallmark electrophysiological properties of endogenous Uniporter channels. Through interrogation of pore-lining mutants, we find that a ring of glutamate residues, the "E-locus," serves as the channel's selectivity filter. Unexpectedly, a nearby "D-locus" at the mouth of the pore has diminutive influence on selectivity. Anomalous mole fraction effects indicate that multiple Ca2+ ions are accommodated within the E-locus. By facilitating ion-ion interactions, the E-locus engenders both exquisite Ca2+ selectivity and high ion throughput. Direct comparison with structural information yields the basis for selective Ca2+ conduction by the channel. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less