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

• Published in: The FASEB journal Vol. 38; no. 3; pp. e23454 - n/a
• Main Authors: Ramos, Vitor M., Serna, Julian D. C., Vilas‐Boas, Eloisa A., Cabral‐Costa, João Victor, Cunha, Fernanda M., Kataura, Tetsushi, Korolchuk, Viktor I., Kowaltowski, Alicia J.
• Format: Journal Article
• Language: English
• Published: United States 15-02-2024
• Subjects: Autophagy; autophagy regulation; Calcium - metabolism; Calcium Signaling - physiology; calcium transport; caloric restriction; Clonazepam - analogs & derivatives; hepatocytes; mitochondria; Mitochondria - metabolism; NCLX; Sodium - metabolism; Sodium-Calcium Exchanger; Thiazepines; autophagy regulation; caloric restriction; NCLX; mitochondria; calcium transport; hepatocytes
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202301368RR

Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+/Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+, 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 Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.
Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate hepatic NCLX expression in vivo and in cellula. Knockdown of NCLX as well as pharmacological inhibition impair autophagy activation. Mechanistically, decreased NCLX activity causes impaired intracellular Ca2+ signaling, which is required for the formation of the FIP200 complex and downstream autophagosome biogenesis.