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 () and Orian S. Shirihai ()
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Essam A. Assali: University of California Los Angeles
Anthony E. Jones: University of California Los Angeles
Michaela Veliova: University of California Los Angeles
Rebeca Acín-Pérez: University of California Los Angeles
Mahmoud Taha: Ben-Gurion University
Nathanael Miller: University of California Los Angeles
Michaël Shum: University of California Los Angeles
Marcus F. Oliveira: Universidade Federal do Rio de Janeiro
Guy Las: Ben-Gurion University
Marc Liesa: University of California Los Angeles
Israel Sekler: Ben-Gurion University
Orian S. Shirihai: University of California Los Angeles

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16572-3

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