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

Assali, E. A.; Jones, A. E.; Veliova, M.; Taha, M.; Miller, N.; Shum, M.; Oliveira, M. F.; Las, G.; Liesa, M.; Sekler, I.; Shirihai, O. S.

doi:10.1101/464339

bioRxiv · 10.1101/464339

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

Assali, E. A.·Jones, A. E.·Veliova, M.·Taha, M.·Miller, N.·Shum, M.·Oliveira, M. F.·Las, G.·Liesa, M.·Sekler, I.·Shirihai, O. S.

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Abstract

A sharp increase in mitochondrial Ca2+ marks the activation of the 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-ablated brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging and VO2 measurements confirm a BAT specific thermogenic defect in NCLX-null mice.\n\nWe show that mitochondrial Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the opening of the mitochondrial permeability transition pore (mPTP), leading to remarkable mitochondrial swelling, Cytochrome c release and cell death in BAT. However, treatment with mPTP inhibitors rescue mitochondrial respiratory function and thermogenesis in NCLX-null BA, in vitro and in vivo.\n\nOur findings identify a novel pathway enabling non-lethal mitochondrial Ca2+ elevation during adrenergic stimulation of uncoupled respiration. Deletion of NCLX transforms the adrenergic pathway responsible for the stimulation of thermogenesis into a death pathway.

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Assali, E. A., Jones, A. E., Veliova, M., Taha, M., Miller, N., Shum, M., Oliveira, M. F., Las, G., Liesa, M., Sekler, I., Shirihai, O. S.. 2018-11-06. NCLX prevents cell death during adrenergic activation of the brown adipose tissue. https://doi.org/10.1101/464339

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