OPTOGENETIC ACCELERATION OF MITOCHONDRIAL METABOLISM IN THE MAMMALIAN SYNAPSE

The trade-offs between information processing and energy consumption have influenced the evolution of neurons and neural circuits, favoring submaximal information processing to minimize excess energy consumption without clear behavioral benefits. However, this implies that in healthy states, there is potential to increase neural circuit function, and thus the nervous system's diverse tasks could be improved by alleviating the metabolic constraints that limit neuronal and circuit performance. However, the brain's intense energy demand, along with the extensive biosynthetic requirements of different neuronal populations, makes brain metabolism exceptionally complex. Despite substantial progress in this field in recent years, driven by sophisticated in vivo imaging and advanced metabolomics, our understanding of neuronal metabolism remains limited. A plethora of neurodegenerative diseases like Alzheimer’s and Parkinson’s, and neuropsychiatric disorders from MDD to schizophrenia show significant disruptions of mitochondrial function and metabolic homeostasis in the brain. However, we don't yet understand whether dysregulated metabolism is the driving force or merely an outcome of abnormal circuit function in these diseases. Largely because we don't have effective molecular tools to upregulate or downregulate metabolism in mammalian systems with spatiotemporal resolution. Our ongoing work is close to filling this gap by developing a set of optogenetic channels that selectively localize to the inner mitochondrial membrane. We have optimised strategies for successful targeting, topological inversion, and folding of CapChR2, a calcium-selective Opsin, in its functional form. Light-activated controlled entry of Calcium into the Mitochondrial matrix accelerates the TCA cycle, resulting in increased metabolic flux and ATP production.