Mitochondrial Complex I and ROS control synapse function through opposing pre- and postsynaptic mechanisms

Neurons require high amounts energy, and mitochondria help to fulfill this requirement. Dysfunc-tional mitochondria trigger problems in various neuronal tasks. Using the Drosophila neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here we report tissue-specific ad-aptations at the NMJ when MCI is depleted. In Drosophila motor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But in-stead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destruc-tive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmis-sion. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in the Drosophila system are potentially relevant to forms of mitochondrial pathogenesis.