Optometabolic and molecular analysis of functional links between mitochondrial CA2+signaling, gene regulation and metabolism in the brain

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Mitochondria are the only organelles that combine energy control with the critical role in the maintenance of Ca2+ homeostasis. Powered by the same steep membrane potential that drives ATP synthesis, Ca2+ ions are taken into mitochondria by Ca2+ uniporter, MCU, and extruded back to the cytosol primarily by the Na+/Ca2+ antiporter, NCLX. Proper mitochondrial metabolism and Ca2+ shuttling are essential for maintenance of a range of neuronal activities. Under pathologic conditions, mitochondrial dysfunction causes a series of vicious cycles that lead to irreversible neuronal damage. Studies of the role of mitochondria in neurons, however, are impeded by the insufficient precision and reversibility of available pharmacological agents. Here, we propose (1) to take advantage of our team’s recent discovery of the molecular identity of MCU and NCLX to devise specific molecular tools to control the mitochondrial function and (2) to establish a novel optogenetic (optometabolic) strategy based on targeting light-activated ion channels to the mitochondrial matrix, to control by light mitochondrial membrane potential and thereby ATP synthesis and Ca2+ shuttling. Using the combined optometabolic-molecular approach, we will determine (1) how mitochondria shape dendritic-nuclearCa2+ signaling and neuronal gene expression, (2) if MCU/NCLX degradation or dysregulation affects neuronal functional properties and fate during ischemia, (3) how fast and transient changes in mitochondrial membrane potential control neurotransmission between individual neurons and (4) communications within and between brain areas. Implementation of the optometabolic and molecular technologies will enable control of the mitochondrial membrane potential and thereby of the Ca2+ signaling and metabolic rate in a temporallycontrolled, reversible and cell-specific way, both in vitro and in vivo, and therefore will be also of general importance for investigating metabolic and ischemic disorders ranging from brain or cardiac ischemia to Diabetes.