@article{9422b7536ef743aab6811f4b998bdb44,
title = "NCLX prevents cell death during adrenergic activation of the brown adipose tissue",
abstract = "A sharp increase in mitochondrial Ca2+ marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca2+ extrusion via the mitochondrial Na+/Ca2+ exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO2 measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the mitochondrial permeability transition pore (mPTP) opening, leading to a remarkable mitochondrial swelling and cell death. Treatment with mPTP inhibitors rescue mitochondrial function and thermogenesis in NCLX-null BAT, while calcium overload persists. Our findings identify a key pathway through which BA evade apoptosis during adrenergic stimulation of uncoupling. NCLX deletion transforms the adrenergic pathway responsible for thermogenesis activation into a death pathway.",
author = "Assali, {Essam A.} and Jones, {Anthony E.} and Michaela Veliova and Rebeca Ac{\'i}n-P{\'e}rez and Mahmoud Taha and Nathanael Miller and Micha{\"e}l Shum and Oliveira, {Marcus F.} and Guy Las and Marc Liesa and Israel Sekler and Shirihai, {Orian S.}",
note = "Funding Information: The authors would like to thank those who contributed helpful discussions, insight, and support of the research, including Drs. Kiana Mahdaviani, Ilan Benador, Eleni Ritou, Evan Taddeo, Linsey Stiles, Nour Alsabeeh, Anton Petcherski, Fernanda Cerqueira, Jennifer Ngo, and Kyle Trudeau from the Shirihai lab and Drs. Marko Kostic, Soumitra Roy, Tatiana Tkatch, and Tomer Katoshevski from Sekler lab. The authors would like to thank Drs. Assaf Rudich, Alicia Kowaltowski, Dani Dagan, Jan Nedergaard, Barbara Cannon, Barbara Corkey, Marc Prentki, Michal Hershfinkel, Ajit Divakaruni, Ehud Ohana, and Daniel Khananshvili for their helpful advice and discussions. We thank Dr. Jason T. Lee and Charles Zamilpa at UCLA{\textquoteright}s Crump Imaging Technology Center for assistance with PET/CT imaging of the mice. We thank Translational Pathology Core Laboratory at UCLA{\textquoteright}s DGSOM for assistance with histology samples preparation and processing and we thank Dr. Chunni Zhu from the electron microscopy core at the Brain Research Institute, UCLA for her assistance with electron microscopy acquisition and sample preparation. Graphical illustrations were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License. E.A.A. is an Azrieli fellow and was supported by the Kreitman predoctoral scholarship from Ben-Gurion University and the Israeli Council for Higher Education fellowship. O.S.S. is funded by National Institutes of Health grants RO1 DK35914, R01 DK56690, and R01 DK074778. I.S. is funded by Israel Science Foundation (ISF, 1424/17), ISF-China (1210/14), and German-Israeli Project Cooperation (DIP, SE2372/1-1). M.L. is funded by the DRC UCLA/UCSD Pilot grant (NIH P30 DK063491) and the Department of Medicine Chair at UCLA. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "https://doi.org/10.1038/s41467-020-16572-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}