[R01] Exploring activity-dependent regulation of intra and intercellular mitochondrial transport in astrocytes

Ente: National Institute of Neurological Disorders and Stroke

Scadenza: 2030-07-31

Importo max: 432.582 EUR

Paese: US

Descrizione

PROJECT SUMMARY Brain function is dependent on the precise wiring of distinct neuron types into functional neural circuits. Neurons communicate with each other through synapses, which are carefully monitored and supported by specialized non-neuronal cells called glia. Astrocytes are a prominent, peri-synaptic glial cell population that regulates synapse development, synapse stability, and neuronal signaling. As neuronal signaling is an energetically demanding process, one critical function of astrocytes is to support the metabolic needs of neighboring neurons. In the healthy nervous system, astrocytes are known to shuttle lactate directly to neurons to facilitate neuronal respiration and ATP generation. Recent data suggests that under pathological conditions, astrocytes can also transfer entire mitochondria to damaged or diseased neurons to boost neuronal metabolism and restore neuronal function. Whether astrocytes donate mitochondria to neurons under homeostatic conditions is not clear. Furthermore, the mechanisms used by neurons to stimulate intercellular transport of astrocytic mitochondria are poorly defined. Mitochondrial dysfunction is a hallmark of normal aging that is accelerated in neurodegenerative disease; thus, understanding the cellular and molecular mechanisms used by astrocytes to support neuronal metabolism is a key knowledge gap that impedes our ability to rejuvenate the brain. To explore astrocyte-neuron metabolic coupling, we leverage Drosophila as a system where we have precise genetic access to neurons and associated astrocytes, where we have sophisticated genetic tools for optogenetic and thermogenetic manipulation of neuronal activity, and where we have a wealth of transgenic tools for visualizing mitochondrial location and function. We found that stimulating motor neuron activity is sufficient to recruit astrocyte mitochondria towards neuronal synapses and can induce astrocyte-to-neuron intercellular transport of mitochondria. Moreover, we found that astrocyte-specific knockdown of the mitochondrial adaptor milton completely blocked entry of astrocyte mitochondria into the synapse-rich neuropil, resulting in reduced motor neuron activity and defective locomotor behavior. In this proposal, we continue to leverage this model system to understand (Aim 1) what are the cellular mechanisms that position astrocyte mitochondria near neuronal synapses and (Aim 2) facilitate astrocyte-to-neuron mitochondria transport. Finally, we aim to identify the neuronal-activity induced cues that trigger intercellular transport of astrocyte mitochondria (Aim 3). Ultimately, we hope that a better understanding of the cellular and molecular mechanisms that couple astrocyte and neuronal metabolism will enhance our ability to alleviate circuit dysfunction in neurodegenerative disease. Istituzione: WASHINGTON UNIVERSITY PI: Sarah D Ackerman Progetto: 5R01NS144659-02

Settori: National Institute of Neurological Disorders and Stroke

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