Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, 84103, Israel.
Nat Commun. 2020 Jul 3;11(1):3347. doi: 10.1038/s41467-020-16572-3.
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.
线粒体钙的急剧增加标志着棕色脂肪组织（BAT）产热的激活，但防止钙产生有害影响的机制还知之甚少。在这里，我们表明，去甲肾上腺素对 BAT 的刺激通过线粒体 Na/Ca 交换体 NCLX 激活依赖于蛋白激酶 A 的线粒体钙外排。去甲肾上腺素对 NCLX 缺失的棕色脂肪细胞（BA）的刺激诱导严重的线粒体钙过载和解偶联呼吸受损。核心体温、葡萄糖摄取的 PET 成像和 VO 测量证实了 NCLX 缺失小鼠的产热缺陷。我们表明，去甲肾上腺素刺激 NCLX 缺失 BAT 引起的钙过载，触发线粒体通透性转换孔（mPTP）的打开，导致明显的线粒体肿胀和细胞死亡。mPTP 抑制剂的治疗可挽救 NCLX 缺失 BAT 的线粒体功能和产热，而钙过载持续存在。我们的研究结果确定了一条关键途径，通过该途径，BA 在去偶联的去甲肾上腺素刺激下逃避细胞凋亡。NCLX 缺失将负责产热激活的肾上腺素能途径转化为死亡途径。
