Mitochondrial dysfunction: Glucokinase downregulation lowers interaction of glucokinase with mitochondria, resulting in apoptosis of pancreatic β-cells

June Woo Lee, Won Ho Kim, Joo Hyun Lim, Eun Hyeon Song, Jihyun Song, Kang Yuel Choi, Myeong Ho Jung

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Mitochondrial dysfunction has been considered a critical component in the development of diabetes. In pancreatic β-cells especially, mitochondrial dysfunction impairs insulin secretion and the eventual apoptosis of β-cells. The aim of this study was to elucidate the molecular mechanism underlying these events. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, a mouse pancreatic β-cells, and the effects of glucokinase (GCK) and mitochondria were investigated. Concurrent with reduction in mitochondrial membrane potential (ΔΨm) and cellular ATP content, impaired mitochondrial function reduced GCK expression and resulted in decreased insulin secretion and β-cell apoptosis. Specifically, lowered GCK expression led to decreased interactions between GCK and mitochondria, which increased Bax binding to mitochondria and cytochrome C release into cytoplasm. However, these events were blocked by treatment with the antioxidant, N-acetyl-cysteine (NAC), as well as GCK overexpression. Moreover, examination of the GCK promoter in antimycin-treated cells demonstrated that the promoter region within - 287 bases from transcription site is involved in the transcriptional repression of GCK by mitochondrial stress, whose region contains a putative binding site for pancreatic duodenal homeobox-1 (PDX-1). Mitochondrial stress reduced PDX-1 expression, and increased ATF3 expression dependent on reactive oxygen species (ROS). Collectively, these data demonstrate that mitochondrial dysfunction by metabolic stress reduces GCK expression through PDX-1 downregulation via production of ROS, which then decreases the association of GCK with mitochondria, resulting in pancreatic β-cell apoptosis and reduction of insulin secretion.

Original languageEnglish
Pages (from-to)69-78
Number of pages10
JournalCellular Signalling
Volume21
Issue number1
DOIs
Publication statusPublished - 2009 Jan

All Science Journal Classification (ASJC) codes

  • Cell Biology

Fingerprint Dive into the research topics of 'Mitochondrial dysfunction: Glucokinase downregulation lowers interaction of glucokinase with mitochondria, resulting in apoptosis of pancreatic β-cells'. Together they form a unique fingerprint.

  • Cite this