Final Report Summary - FUELLINGSYNAPSES (Regulation of neuronal connectivity and plasticity by activity-dependent mitochondrial trafficking to synapses) Nerve cells send signals to each other by releasing chemicals called neurotransmitters from the axon of one neuron onto another neurons dendritic tree at special sites called synapses. The neurotransmitters act on receptor proteins, allowing ions to cross the cell membrane, thus producing voltage changes across the membrane. For neurons to continue signalling to each other, it is essential that they pump the ions back across the membrane, and for this they need a constant energy supply, generated by microscopic power stations within the cell called mitochondria. Mitochondria can be moved around cells by small motors, on intracellular protein tracks called microtubules. The linkage of mitochondria to these motors is mediated by GTPase proteins called Miro1 and Miro2. The purpose of the project was to shed light on the mechanisms by which Miro proteins regulate mitochondrial distribution within cells and reciprocally how mitochondrial positioning is important for cell function, neuronal signaling and pathology. To study the basic properties of the Miro machinery we performed some experiments in simple fibroblast cells where we removed both Miro1 and Miro2. Unexpectedly, this revealed that Miro proteins can also couple mitochondria to a different cytoskeleton called actin, through specialist motors called myosins. In neurons we showed that mitochondrial positioning was important for building the brain by regulating the formation of the complex dendrite arborisation as the brain develops and also for maintaining the dendritic arbors in the adult. We also showed mitochondria are important for regulating the amount of neurotransmitter released from axons to regulate the strength of the synapse. We also investigating the role of Miro proteins in neurological and neurodegenerative diseases. We found that if mitochondria were depleted from dendrites in the adult, the dendrites eventually retracted back, leading to neurodegeneration, a process relevant to Alzheimer’s disease. We also found Miro proteins linked to Parkinson's disease and to the function of disease genes linked to susceptibility to Schizophrenia. Our studies have significantly advanced understanding of the molecular mechanisms that control mitochondrial localisation in neurons and glial cells and the role that activity-dependent mitochondrial trafficking plays in regulating neuronal development and function, and dysfunction in neurodegenerative and neuropsychiatric disorders.