NCLX prevents cell death during adrenergic activation of the brown adipose tissue

Essam A Assali; Anthony E Jones; Michaela Veliova; Rebeca Acín-Pérez; Mahmoud Taha; Nathanael Miller; Michaël Shum; Marcus F Oliveira; Guy Las; Marc Liesa; Israel Sekler; Orian S Shirihai

doi:10.1038/s41467-020-16572-3

NCLX prevents cell death during adrenergic activation of the brown adipose tissue

Nat Commun. 2020 Jul 3;11(1):3347. doi: 10.1038/s41467-020-16572-3.

Authors

Essam A Assali^{1

2

3

4}, Anthony E Jones³, Michaela Veliova^{1

3}, Rebeca Acín-Pérez^{1

3}, Mahmoud Taha⁴, Nathanael Miller^{1

3}, Michaël Shum¹, Marcus F Oliveira⁵, Guy Las², Marc Liesa^{1

3}, Israel Sekler⁶, Orian S Shirihai^{7

8

9}

Affiliations

¹ Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
² Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84103, Israel.
³ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁴ Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84105, Israel.
⁵ Institute of Medical Biochemistry Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
⁶ Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84105, Israel. sekler@bgu.ac.il.
⁷ Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. Oshirihai@mednet.ucla.edu.
⁸ Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84103, Israel. Oshirihai@mednet.ucla.edu.
⁹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. Oshirihai@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Adipocytes, Brown / cytology
Adipocytes, Brown / drug effects
Adipocytes, Brown / pathology*
Adipose Tissue, Brown / cytology
Adipose Tissue, Brown / metabolism*
Adrenergic Agents / pharmacology
Animals
Apoptosis / drug effects
Calcium / metabolism
Cells, Cultured
Cold Temperature / adverse effects
Cyclosporine / pharmacology
Energy Metabolism / drug effects
Energy Metabolism / physiology
Female
Intravital Microscopy
Male
Mice
Mice, Knockout
Microscopy, Fluorescence
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Permeability Transition Pore
Norepinephrine / metabolism*
Primary Cell Culture
Signal Transduction
Sodium-Calcium Exchanger / genetics
Sodium-Calcium Exchanger / metabolism*
Thermogenesis / drug effects
Thermogenesis / physiology*

Substances

Adrenergic Agents
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Slc8b1protein, mouse
Sodium-Calcium Exchanger
Cyclosporine
(melle-4)cyclosporin
Calcium
Norepinephrine

Abstract

Publication types

MeSH terms

Substances

Grants and funding