ERAD deficiency disrupts mitochondrial bioenergetics by altering MAM Ca2+ in human hepatic cells

Mitochondria and the endoplasmic reticulum (ER) physically and functionally interact, regulating each other’s function, but the molecular mechanisms remain not fully understood. In this study, we revealed that ER-associated degradation (ERAD), an ER protein quality control mechanism, governs ER Ca2+ entry into mitochondria by mitochondria-associated ER membrane (MAM) in hepatic cells. Inhibition of ERAD by pharmaceuticals or genetic ablation of the key ERAD protein SEL1L resulted in altered mitochondrial morphology, reduced mitochondrial energy production, and increased Ca2+ transfer from ER to mitochondria. Additionally, SEL1L absence caused an increase in the number of MAM. In ERAD-deficient hepatic cells, a reduction in the number of MAM or knockdown of the inositol 1,4,5-trisphosphate receptor (IP3R), which is responsible for ER Ca2+ release, partially restored mitochondrial Ca2+ signaling and bioenergetics. Together, these results suggest that ERAD plays a crucial role in regulating mitochondrial bioenergetics, suggesting the potential to improve cellular and organismal mitochondrial function by increasing cellular ERAD activity.