Mitochondrial Ca2+ Uptake Relieves PalmitateInduced Cytosolic Ca2+ Overload in MIN6 Cells

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)66-75
Number of pages10
JournalMolecules and cells
Volume43
Issue number1
DOIs
Publication statusPublished - 2020 Jan 31

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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