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

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