Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1 alpha as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1 alpha deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1 alpha determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1 alpha at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1 alpha conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1 alpha in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.