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Ly, Luong Dai,Ly, Dat Da,Nguyen, Nhung Thi,Kim, Ji-Hee,Yoo, Heesuk,Chung, Jongkyeong,Lee, Myung-Shik,Cha, Seung-Kuy,Park, Kyu-Sang Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.1
Saturated fatty acids contribute to β-cell dysfunction in the onset of type 2 diabetes mellitus. Cellular responses to lipotoxicity include oxidative stress, endoplasmic reticulum (ER) stress, and blockage of autophagy. Palmitate induces ER Ca<sup>2+</sup> depletion followed by notable store-operated Ca<sup>2+</sup> entry. Subsequent elevation of cytosolic Ca<sup>2+</sup> can activate undesirable signaling pathways culminating in cell death. Mitochondrial Ca<sup>2+</sup> uniporter (MCU) is the major route for Ca<sup>2+</sup> uptake into the matrix and couples metabolism with insulin secretion. However, it has been unclear whether mitochondrial Ca<sup>2+</sup> uptake plays a protective role or contributes to lipotoxicity. Here, we observed palmitate upregulated MCU protein expression in a mouse clonal β-cell, MIN6, under normal glucose, but not high glucose medium. Palmitate elevated baseline cytosolic Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and reduced depolarization-triggered Ca<sup>2+</sup> influx likely due to the inactivation of voltage-gated Ca<sup>2+</sup> channels (VGCCs). Targeted reduction of MCU expression using RNA interference abolished mitochondrial superoxide production but exacerbated palmitate-induced [Ca<sup>2+</sup>]<sub>i</sub> overload. Consequently, MCU knockdown aggravated blockage of autophagic degradation. In contrast, co-treatment with verapamil, a VGCC inhibitor, prevented palmitate-induced basal [Ca<sup>2+</sup>]<sub>i</sub> elevation and defective [Ca<sup>2+</sup>]<sub>i</sub> transients. Extracellular Ca<sup>2+</sup> chelation as well as VGCC inhibitors effectively rescued autophagy defects and cytotoxicity. These observations suggest enhanced mitochondrial Ca<sup>2+</sup> uptake via MCU upregulation is a mechanism by which pancreatic β-cells are able to alleviate cytosolic Ca<sup>2+</sup> overload and its detrimental consequences.