Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance

Lauren E. Wright, Denis Vecellio Reane, Gabriella Milan, Anna Terrin, Giorgia Di Bello, Anna Belligoli, Marta Sanna, Mirto Foletto, Francesca Favaretto, Anna Raffaello, Cristina Mammucari, Donato Nitti (+2 others)
2017 American Journal of Physiology. Endocrinology and Metabolism  
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 2ϩ 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
more » ... ne 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 2ϩ ] mt ) 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 2ϩ ]mt and the release of IL-6 and TNF␣ 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. mitochondrial calcium; MCU; obesity; inflammation CALCIUM IS A FUNDAMENTAL PLAYER in a wide range of intracellular signaling events, including the direct regulation of several metabolic enzymes (17). Intracellular calcium can modulate de novo lipogenesis in rodents and humans (53),
doi:10.1152/ajpendo.00143.2016 pmid:28790027 fatcat:wbr2poans5clnlho2i5lxbfoyi