SEC24A facilitates colocalization and Ca flux between the endoplasmic reticulum and mitochondria.

A genome-wide screen recently identified SEC24A as a novel mediator of thapsigargin-induced cell death in HAP1 cells. Here, we determined the cellular mechanism and specificity of SEC24A-mediated cytotoxicity. Measurement of Ca levels using organelle-specific fluorescent indicator dyes showed that Ca efflux from endoplasmic reticulum (ER) and influx into mitochondria were significantly impaired in -knockout cells. Furthermore, knockout cells also showed ∼44% less colocalization of mitochondria and peripheral tubular ER. Knockout of , but not its paralogs , or , rescued HAP1 cells from cell death induced by three different inhibitors of sarcoplasmic/endoplasmic reticulum Ca ATPases (SERCA) but not from cell death induced by a topoisomerase inhibitor. Thapsigargin-treated -knockout cells showed a ∼2.5-fold increase in autophagic flux and ∼10-fold reduction in apoptosis compared to wild-type cells. Taken together, our findings indicate that SEC24A plays a previously unrecognized role in regulating association and Ca flux between the ER and mitochondria, thereby impacting processes dependent on mitochondrial Ca levels, including autophagy and apoptosis.