Nr1d1 regulates ER-mitochondria interactions and calcium transfer, and muscle cell apoptosis.

The Endoplasmic Reticulum (ER) and mitochondria interact within specific structures called Mitochondria-ER Contact sites (MERCs). MERCs are involved in calcium exchange and apoptosis. However, factors controlling MERC formation and functions are not fully identified. Since the nuclear receptor Nr1d1 (also known as Rev-erbα) modulates both mitochondrial function and reticular calcium homeostasis in skeletal muscle, we explored whether Nr1d1 could also impact MERC formation and as such modulate calcium fluxes and apoptosis of muscle cells upon ER stress.Here, we observe that Nr1d1 overexpression in C2C12 muscle cells and human myotubes increases MERC formation, favoring calcium transfer from the ER toward mitochondria. Upon tunicamycin-induced ER stress, Nr1d1 overexpression causes greater calcium influx into mitochondria, subsequently triggering a deeper reduction in mitochondrial efficiency and exacerbating apoptosis. Pharmacological inhibition of MERCs formation partly abolishes Nr1d1 effects on ER stress-induced calcium transfer and apoptosis.These findings identify Nr1d1 as a new modulator of MERCs in muscle cells.