Powering the Brain: Understanding how Astrocytes Contribute to Energy Maintenance

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The brain is the most energy expensive organ in the human body. To provide sufficient energy, neurons and glial cells harness oxidative phosphorylation in mitochondria to produce up to 90% of ATP required for cellular physiology. Remarkably, astrocytes, a highly specialized glial cell surrounding neurons, account for approximately 75% of ATP produced in the brain. The robust ATP production by astrocytes supports energy-consuming processing including extracellular ion maintenance, neurotransmitter homeostasis, and energy substrate transport from cerebrovasculature. Despite the known importance of energy production by astrocytes, fundamental aspects of this process in vivo remain unclear. Further investigation is need to resolve how these cells create, store, and distribute energy to maintain the structural and physiological integrity of cells in the brain. In this Discovery Research Program, we will study fundamental properties of astrocyte mitochondria using advanced in vivo gene delivery methods combined with cutting-edge imaging, molecular, and electrophysiology approaches.******In Aim 1, we will use advanced methods to characterize mitochondria size, shape, and distribution in astrocytes and their cellular compartments (i.e. soma, distal processes, and endfeet) using cutting-edge light and electron microscopy approaches. Preliminary results indicate a complex organization of mitochondria in astrocytes in situ. Results from the proposed experiments will describe for the first time the 3-dimensional organization of mitochondria within individual astrocytes in the brain.******In Aim 2, we will use live imaging approaches to monitor mitochondrial trafficking in astrocytes in situ and determine how neural activity and intracellular calcium dynamics in astrocytes relates to mitochondrial transport, fission/fusion events, and local recruitment to specific compartments. Preliminary results suggest that mitochondria are enriched at areas of high calcium dynamics in astrocytes. 2-photon imaging will be used to monitor these processes in the intact mouse brain.******In Aim 3, we will identify mitochondrial trafficking components in astrocytes. We will initially focus on the trafficking protein kinesin binding 1 (TRAK1) and 2 (TRAK2) proteins in astrocytes that help target mitochondria in neurons. Preliminary results indicate specific mechanisms are used for mitochondrial targeting in astrocytes. We will determine how perturbation of mitochondrial trafficking in astrocytes impacts their anatomy and molecular features, as well as, the physiology of neighboring neurons.******This grant will create a new level of understanding of astrocyte mechanisms that control energy delivery within the brain. Moreover, it will provide excellent conceptual and technical training for trainees at all levels interested in understanding fundamental aspects of brain function and homeostasis.