Mitochondrial Ca2+ Uptake Relieves PalmitateInduced Cytosolic Ca2+ Overload in MIN6 Cells
Luong Dai Ly1,2, Dat Da Ly1,2, Nhung Thi Nguyen1,2, Ji-Hee Kim2, Heesuk Yoo3, Jongkyeong Chung3, Myung-Shik Lee4,5, Seung-Kuy Cha1,2, and Kyu-Sang Park1,2,*
1Department of Physiology, 2Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Korea, 3National Creative Research Initiatives Center for Energy Homeostasis Regulation, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Korea, 4Severance Biomedical Science Institute, 5Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
Received September 27, 2019; Revised November 20, 2019; Accepted December 3, 2019.; Published online January 13, 2020.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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 Ca2+ depletion followed by notable store-operated Ca2+ entry. Subsequent elevation of cytosolic Ca2+ can activate undesirable signaling pathways culminating in cell death. Mitochondrial Ca2+ uniporter (MCU) is the major route for Ca2+ uptake into the matrix and couples metabolism with insulin secretion. However, it has been unclear whether mitochondrial Ca2+ 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 Ca2+ concentration ([Ca2+]i) and reduced depolarization-triggered Ca2+ influx likely due to the inactivation of voltage-gated Ca2+ channels (VGCCs). Targeted reduction of MCU expression using RNA interference abolished mitochondrial superoxide production but exacerbated palmitate-induced [Ca2+]i overload. Consequently, MCU knockdown aggravated blockage of autophagic degradation. In contrast, co-treatment with verapamil, a VGCC inhibitor, prevented palmitate-induced basal [Ca2+]i elevation and defective [Ca2+]i transients. Extracellular Ca2+ chelation as well as VGCC inhibitors effectively rescued autophagy defects and cytotoxicity. These observations suggest enhanced mitochondrial Ca2+ uptake via MCU upregulation is a mechanism by which pancreatic β-cells are able to alleviate cytosolic Ca2+ overload and its detrimental consequences.
Keywords: cytosolic Ca2+ overload, lipotoxicity, mitochondrial Ca2+ uniporter, oxidative stress, pancreatic β-cell

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31 December 2019 Volume 42,
Number 12, pp. 821~918

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