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

Abstract

Endoplasmic reticulum (ER) and mitochondria form close physical associations to facilitate calcium transfer, thereby regulating mitochondrial function. Neurons with high metabolic demands, such as sensory hair cells, are especially dependent on precisely regulated ER-mitochondria associations. We previously showed that the secreted metalloprotease Pregnancy associated plasma protein-aa (Pappaa) regulates 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. pappaa mutant hair cells are more vulnerable to pharmacological induction of ER-calcium transfer. Additionally, pappaa mutant hair cells display ER stress and dysfunctional downstream processes of the ER-mitochondria axis including altered mitochondrial morphology and reduced autophagy. We further show that Pappaa influences ER-calcium transfer and autophagy via its ability to stimulate insulin-like growth factor-1 bioavailability. Together our results identify Pappaa as a novel regulator of the ER-mitochondria axis.

The role of calcium, Akt and ERK signaling in cadmium-induced hair cell death

“…Another alternative activation route is growth factor signaling. Increases in growth factor receptors have been seen after hair cell damage (Lee and Cotanche, 1996;Zine and de Ribaupierre, 1999), and inhibiting the IGF1R receptor has been shown to also increase susceptibility to aminoglycosideinduced hair cell damage (Alassaf and Halloran, 2021), suggesting a role for growth factor signaling in protecting hair cells from damage.…”