Wright Lauren E, Vecellio Reane Denis, Milan Gabriella, Terrin Anna, Di Bello Giorgia, Belligoli Anna, Sanna Marta, Foletto Mirto, Favaretto Francesca, Raffaello Anna, Mammucari Cristina, Nitti Donato, Vettor Roberto, Rizzuto Rosario
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Endocrine-Metabolic Laboratory, Department of Medicine, University of Padua, Padua, Italy; and.
Am J Physiol Endocrinol Metab. 2017 Dec 1;313(6):E641-E650. doi: 10.1152/ajpendo.00143.2016. Epub 2017 Aug 8.
Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca]) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca] and the release of IL-6 and TNFα in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT.
细胞内钙影响一系列信号通路并影响细胞过程。随着对线粒体钙单向转运体（MCU）复合体的分子特性和生理作用的研究迅速进展，我们现在有了工具来理解线粒体钙在病理生理过程调节中的功能。在此，我们描述关键MCU复合体成分在小鼠和人类脂肪组织胰岛素抵抗中的作用。从几种肥胖和糖尿病啮齿动物模型、72例肥胖患者以及体外胰岛素抵抗脂肪细胞中分析了脂肪组织基因表达。对3T3-L1脂肪细胞中MCU活性进行基因操作，从而能够研究线粒体钙摄取的作用。在胰岛素抵抗脂肪细胞中，线粒体钙摄取增加，并且几种MCU成分上调。在肥胖和糖尿病进展过程中，在小鼠和人类内脏脂肪组织（VAT）中观察到了类似结果。有趣的是，皮下脂肪组织（SAT）未出现明显的MCU波动。此外，通过减肥手术体重减轻后，患者VAT中的MCU表达恢复到生理水平。对3T3-L1脂肪细胞中线粒体钙摄取进行基因操作表明，线粒体钙浓度（[Ca]）的变化可影响线粒体代谢，包括氧化酶活性、线粒体呼吸、膜电位和活性氧生成。最后，我们的数据表明[Ca]与脂肪细胞中白细胞介素-6（IL-6）和肿瘤坏死因子α（TNFα）的释放之间存在密切关系。脂肪细胞中线粒体钙通量的改变可能在肥胖和糖尿病中起作用，并且可能与VAT和SAT的不同代谢特征相关。
