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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Article number3347
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

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