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

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

doi:10.1038/s41467-020-16572-3

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.

Highlights

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
While a rise in mitochondrial calcium has been documented during activation of thermogenesis in BAT, its functional role and regulation has not yet been elucidated
Flicker et al.[20] found that mitochondrial Ca2+ uptake through the mitochondrial calcium uniporter is inconsequential for BAT thermogenic function

Summary

Introduction

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. 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. The brown adipose tissue (BAT) dissipates energy in the form of heat in response to adrenergic stimuli triggered by cold exposure[1,2] This pathway is initiated by the sympathetic neurotransmitter norepinephrine (NE), which induces a PKA-dependent lipid mobilization and oxidation. A recent study that explored mice lacking MCU in BAT found that Ca2+ uptake through MCU is dispensable for BAT-mediated thermogenesis; neither a basal nor a cold-stimulated phenotype were found in these mice[20] This observation, coupled with early mitochondrial Ca2+ studies showing that Na+-dependent mitochondrial Ca2+ extrusion is essential for brown adipocyte (BA) uncoupled respiration[21], bring up the possibility that Ca2+ extrusion rather than entry may be essential in BAT activation. The physiological role of this PKA-dependent regulation is still unclear

Methods

Results

Conclusion