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A sharp increase in mitochondrial Ca 2+  marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca 2+  deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca 2+  extrusion via the mitochondrial Na + /Ca 2+  exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca 2+  overload and impaired uncoupled respiration. Core body temperature, PET imaging of glucose uptake and VO 2  measurements confirm a thermogenic defect in NCLX-null mice. We show that Ca 2+  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.

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