PT  - JOURNAL ARTICLE
AU  - Terri-Leigh Stephen
AU  - Nathalie F. Higgs
AU  - David F. Sheehan
AU  - Sana Al Awabdh
AU  - Guillermo López-Doménech
AU  - I. Lorena Arancibia-Carcamo
AU  - Josef T. Kittler
TI  - Miro1 Regulates Activity-Driven Positioning of Mitochondria within Astrocytic Processes Apposed to Synapses to Regulate Intracellular Calcium Signaling
AID  - 10.1523/JNEUROSCI.2068-15.2015
DP  - 2015 Dec 02
TA  - The Journal of Neuroscience
PG  - 15996--16011
VI  - 35
IP  - 48
4099  - http://www.jneurosci.org/content/35/48/15996.short
4100  - http://www.jneurosci.org/content/35/48/15996.full
SO  - J. Neurosci.2015 Dec 02; 35
AB  - It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity-dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca2+. Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca2+-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca2+ in astrocytic processes. Thus, the regulation of intracellular Ca2+ signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca2+ wave propagation, gliotransmission, and ultimately neuronal function.SIGNIFICANCE STATEMENT Mitochondria are key cellular organelles that play important roles in providing cellular energy and buffering intracellular calcium ions. The mechanisms that control mitochondrial distribution within the processes of glial cells called astrocytes and the impact this may have on calcium signaling remains unclear. We show that activation of glutamate receptors or increased neuronal activity leads to the altered transport of mitochondria and their positioning at synapses dependent on a key mitochondrial trafficking protein called Miro1. We also show that, the control of mitochondrial movement and stopping by Miro plays an important role in regulating astrocyte calcium responses. Thus the regulation of intracellular calcium signaling, by Miro-mediated mitochondrial positioning, could have important consequences for astrocyte signaling and neuron–glial interactions.