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

Author(s)

Ramos, Vitor M. ; Serna, Julian D. C. ; Vilas-Boas, Eloisa A. ; Cabral-Costa, Joao Victor ; Cunha, Fernanda M. ; Kataura, Tetsushi ; Korolchuk, Viktor I. ; Kowaltowski, Alicia J.

• Document type: Journal article
• Source: FASEB JOURNAL; v. 38, n. 3, p. 16-pg., 2024-02-15.

Abstract

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. (AU)

• FAPESP's process: 21/02481-2 - Energy metabolism regulation by mitochondrial Ca2+ transport in the liver
• Grantee: Eloisa Aparecida Vilas Boas
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/05226-3 - Effects of caloric restriction on mitochondrial Ca2+ transport in cardiac and skeletal muscles
• Grantee: Julian David Cualcialpud Serna
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/08581-1 - Mitochondrial calcium transport in nutrient sensing: does NCLX regulate mTORC1 activity?
• Grantee: Vitor de Miranda Ramos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 20/06970-5 - Mitochondrial ion transporters as sensors and regulators in energy metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/14713-0 - Mitochondrial Ca2+ Handling in the Central Nervous System and Energy Metabolism Regulation
• Grantee: João Victor Cabral Costa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/18402-4 - Effects of mitochondrial calcium transport regulation in autophagic process of hepatocytes
• Grantee: Vitor de Miranda Ramos
• Support Opportunities: Scholarships in Brazil - Doctorate