Activity-dependent Mitochondrial ROS Signaling Regulates Recruitment of Glutamate Receptors to Synapses

Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo . In the transparent genetic model Caenorhabditis elegans, we were able to manipulate and measure mitochondrial signaling as well as neuronal activity in vivo . Using this approach, we provide evidence supporting a novel role for mitochondrial signaling in dendrites. Specifically, we show that dendritic mitochondria take up calcium (Ca ²⁺ ) via the mitochondrial Ca ²⁺ uniporter MCU-1 causing an upregulation of mitochondrial reactive oxygen species (mitoROS) production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the C. elegans ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is downregulated by mitoROS signaling resulting from mitochondrial Ca ²⁺ uptake via MCU-1. Thus, postsynaptic mitochondria provide a means of negative feedback that regulates excitatory synapse function which may be vital for neuronal homeostasis by preventing excitotoxicity and energy depletion.