Pregnancy-associated plasma protein-aa promotes neuron survival by regulating mitochondrial function

A neuron’s longevity is regulated by both extracellular molecular factors and the regulation of its intracellular functions, including mitochondrial activity. It remains poorly understood which extracellular factors promote neuron survival by influencing mitochondrial function. Through zebrafish mutant analysis, we reveal a novel extracellular neuronal survival factor: Pregnancy-associated plasma protein-aa (Pappaa). Neurons in pappaa mutant larvae die precociously and exhibit multiple mitochondrial defects, including elevated mitochondrial calcium, membrane potential, and reactive oxygen species production (ROS). In pappaa mutants, neuron loss is exacerbated by stimulation of mitochondrial calcium load or ROS production and suppressed by exposure to a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates local insulin-like growth factor 1 (IGF1) signaling; a known regulator of mitochondrial function and neuron survival. In pappaa mutants, neurons show reduced IGF1-receptor activity and neuron loss is attenuated by stimulation of IGF1 signaling. These results suggest Pappaa-IGF1 signaling promotes neuron survival by regulating mitochondrial function.