TY - JOUR TI - Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function AU - Alassaf, Mroj AU - Daykin, Emily C AU - Mathiaparanam, Jaffna AU - Wolman, Marc A A2 - Raible, David W A2 - Stainier, Didier Y VL - 8 PY - 2019 DA - 2019/06/17 SP - e47061 C1 - eLife 2019;8:e47061 DO - 10.7554/eLife.47061 UR - https://doi.org/10.7554/eLife.47061 AB - To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells’ mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants’ enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function. KW - pregnancy associated plasma protein a KW - hair cell KW - mitochondria KW - IGF signaling KW - oxidative stress JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -