RT Journal Article
SR Electronic
T1 NCLX prevents cell death during adrenergic activation of the brown adipose tissue
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 464339
DO 10.1101/464339
A1 Essam A. Assali
A1 Anthony E. Jones
A1 Michaela Veliova
A1 Mahmoud Taha
A1 Nathanael Miller
A1 Michaël Shum
A1 Marcus F. Oliveira
A1 Guy Las
A1 Marc Liesa
A1 Israel Sekler
A1 Orian S. Shirihai
YR 2018
UL http://biorxiv.org/content/early/2018/11/06/464339.abstract
AB 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.We 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.Our 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.