Autophagy is Regulated by Mitochondrial Calcium Transporters NCLX and MCU

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.17.533187v1?rss=1 Authors: De Miranda Ramos, V., Serna, J. D., Vilas-Boas, E. A., Cabral-Costa, J. V., da Cunha, F. M., Kowaltowski, A. J. Abstract: Autophagy is responsive to intracellular signals, including calcium (Ca2+) ions. Mitochondrial Ca2+ transporters such as the mitochondrial calcium uniporter (MCU, an uptake pathway) and Na+/Li+/Ca2+ exchanger (NCLX, an efflux pathway) are known to shape Ca2+ signals within the cell, thereby regulating Ca2+-sensitive cellular processes. However, the interplay between MCU, NCLX, and autophagy is unknown, and investigating the crosstalk between these important metabolic and signaling nodes was the aim of this study. We evaluated autophagic activity using a wide array of experimental approaches after siRNA-mediated MCU or NCLX knockdown. Under nutrient replete conditions, reduced expression of either NCLX or MCU led to decreased autophagic activity as well as altered expression of several autophagy-related genes, without affecting mitochondrial ATP synthesis. The knockdown of NCLX resulted in marked reduction of LC3 expression and of activation of the AMPK-UKL1 pathway. Interestingly, NCLX expression was increased under autophagy-promoting conditions in vitro and in vivo, demonstrating it is both regulatory of and regulated by autophagic stimuli. Also, genetic and pharmacological inhibition of NCLX caused impaired autophagosome formation and reduced autophagic flux after serum and amino acid starvation. In conclusion, our results uncover an important role for mitochondrial Ca2+ transport as a regulator of both basal and stimulated autophagic activity, modulating both autophagic initiation and autophagossome formation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC