Mitochondrial sodium/calcium exchanger ( NCLX ) regulates basal and starvation‐induced autophagy through calcium signaling

Abstract Mitochondria shape intracellular Ca 2+ signaling through the concerted activity of Ca 2+ uptake via mitochondrial calcium uniporters and efflux by Na + /Ca 2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca 2+ , and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation‐induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER‐phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca 2+ levels, and intracellular Ca 2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca 2+ efflux regulates autophagy through the modulation of Ca 2+ signaling. Collectively, our results show that the mitochondrial Ca 2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.