Nε-(Carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells

Mei Chen Lo, Ming Hong Chen, Wen Sen Lee, Chin I. Lu, Chuang Rung Chang, Shu Huei Kao, Horng Mo Lee

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic β-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGEdamaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with wellorganized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSAinduced mitophage formation. Our study demonstrated that CMLBSA induced mitochondrial dysfunction and mitophagy in pancreatic β-cells. The findings from this study suggest that increased concentration of AGEs may damage β-cells and reduce insulin secretion.

Original languageEnglish
Pages (from-to)829-839
Number of pages11
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume309
Issue number10
DOIs
Publication statusPublished - 2015

Fingerprint

Mitochondrial Degradation
Mitochondrial Dynamics
Bovine Serum Albumin
Thioctic Acid
Insulin
Mitochondria
Proteins
Dynamins
Insulinoma
Advanced Glycosylation End Products
Mitochondrial Membrane Potential
Lipid Peroxides
Autophagy
Mitochondrial DNA
Islets of Langerhans
Adenosine Triphosphate
N(6)-carboxymethyllysine
Cell Line
Autophagosomes

Keywords

  • Advanced glycated end products
  • Diabetes
  • Mitochondrial dynamics
  • Mitophagy

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Nε-(Carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells. / Lo, Mei Chen; Chen, Ming Hong; Lee, Wen Sen; Lu, Chin I.; Chang, Chuang Rung; Kao, Shu Huei; Lee, Horng Mo.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 309, No. 10, 2015, p. 829-839.

Research output: Contribution to journalArticle

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abstract = "Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic β-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGEdamaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with wellorganized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSAinduced mitophage formation. Our study demonstrated that CMLBSA induced mitochondrial dysfunction and mitophagy in pancreatic β-cells. The findings from this study suggest that increased concentration of AGEs may damage β-cells and reduce insulin secretion.",
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AU - Lee, Horng Mo

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