Pregnancy associated plasma protein-aa regulates endoplasmic reticulum-mitochondria associations

The endoplasmic reticulum (ER) and mitochondria form close physical associations to facilitate calcium transfer, thereby regulating mitochondrial function and dynamics. For neurons with high metabolic demands, such as sensory hair cells, precise regulation of ER-mitochondria associations is especially critical for cell survival. We previously identified the secreted metalloprotease Pregnancy associated plasma protein-aa (Pappaa) as a novel regulator of mitochondrial function in zebrafish lateral line hair cells (Alassaf et al., 2019). Here, we show that pappaa mutant hair cells exhibit excessive and abnormally close ER-mitochondria associations, suggesting increased ER-mitochondria calcium transfer. Indeed, we find that pappaa mutant hair cells are more vulnerable to pharmacological induction of ER-calcium release. Additionally, pappaa mutant hair cells display ER stress and dysfunctional downstream processes of the ER-mitochondria axis including mitochondrial fragmentation and autophagy. Together our results support a model in which Pappaa regulates mitochondrial function, at least in part, by regulating ER-mitochondria associations.