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

Authors
 Luong Dai Ly  ;  Dat Da Ly  ;  Nhung Thi Nguyen  ;  Ji-Hee Kim  ;  Heesuk Yoo  ;  Jongkyeong Chung  ;  Myung-Shik Lee  ;  Seung-Kuy Cha  ;  Kyu-Sang Park 
Citation
 MOLECULES AND CELLS, Vol.43(1) : 66-75, 2020 
Journal Title
 MOLECULES AND CELLS 
ISSN
 1016-8478 
Issue Date
2020
MeSH
Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/chemistry ; Biofilms* ; Biomass ; Cations ; Cell Membrane/metabolism ; Drug Carriers ; Drug Delivery Systems* ; Drug Design ; Durapatite/chemistry ; Farnesol/chemistry* ; Glucans/chemistry ; Hydrogen-Ion Concentration ; Micelles ; Microscopy, Confocal ; Nanoparticles/chemistry* ; Polymers/chemistry ; Pyrimidines/chemistry ; Quaternary Ammonium Compounds/chemistry ; Streptococcus mutans/metabolism
Keywords
cytosolic Ca2+ overload ; lipotoxicity ; mitochondrial Ca2+ uniporter ; oxidative stress ; pancreatic β-cell
Abstract
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.
Files in This Item:
T202000356.pdf Download
DOI
10.14348/molcells.2019.0223
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175315
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