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 language | English |
|---|---|
| Pages (from-to) | 829-839 |
| Number of pages | 11 |
| Journal | American Journal of Physiology - Endocrinology and Metabolism |
| Volume | 309 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Nε-(Carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells
AU - Lo, Mei Chen
AU - Chen, Ming Hong
AU - Lee, Wen Sen
AU - Lu, Chin I.
AU - Chang, Chuang Rung
AU - Kao, Shu Huei
AU - Lee, Horng Mo
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Advanced glycated end products
KW - Diabetes
KW - Mitochondrial dynamics
KW - Mitophagy
UR - http://www.scopus.com/inward/record.url?scp=84947230056&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947230056&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00151.2015
DO - 10.1152/ajpendo.00151.2015
M3 - Article
C2 - 26394662
AN - SCOPUS:84947230056
VL - 309
SP - 829
EP - 839
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 10
ER -