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Mitochondrial Ca2+ Uptake Relieves Palmitate-Induced Cytosolic Ca2+ Overload in MIN6 Cells.


ABSTRACT: Saturated fatty acids contribute to ?-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 ?-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 ?-cells are able to alleviate cytosolic Ca2+ overload and its detrimental consequences.

SUBMITTER: Ly LD 

PROVIDER: S-EPMC6999716 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mitochondrial Ca<sup>2+</sup> Uptake Relieves Palmitate-Induced Cytosolic Ca<sup>2+</sup> Overload in MIN6 Cells.

Ly Luong Dai LD   Ly Dat Da DD   Nguyen Nhung Thi NT   Kim Ji-Hee JH   Yoo Heesuk H   Chung Jongkyeong J   Lee Myung-Shik MS   Cha Seung-Kuy SK   Park Kyu-Sang KS  

Molecules and cells 20200101 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 Ca2+ can activate undesirable signaling pathways culminating in cell death. Mitochondrial Ca2+ uniporter (MCU) is the major route for Ca2+ up  ...[more]

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