UC San Diego

Endoplasmic reticulum (ER) stress strongly induces pseudokinase TRB3 in pancreatic beta cells and is associated with mitochondrial dysfunction and death. The mechanism by which ER stress is communicated to mitochondria is not well understood. We examined the molecular mechanism by which TRB3 communicates ER stress presence to mitochondria and found TRB3 localized to mitochondria-associated ER membranes, or MAMs, a major hub of communication between the ER and mitochondria. TRB3 interacts with GRP75, an important link between IP3R on the ER to VDAC on the mitochondria to form the IP3R-GRP75-VDAC complex, an apparatus of calcium transfer from ER to mitochondria. The central finding of this study is that TRB3 plays an integral role in modulating calcium transfer proteins associated with ER-mitochondria calcium transfer – increasing, and thereby setting the stage for mitochondria dysfunction.