Dynamin-related protein 1 mediates high glucose induced pancreatic beta cell apoptosis

Men, Xiuli; Wang, Haiyan; Li, Mi; Cai, Hao; Xu, Shiqin; Zhang, Wenjian; Xu, Yang; Ye, Liya; Yang, Wenying; Wollheim, Claes B.; Lou, Jinning

doi:10.1016/j.biocel.2008.08.031

Cited by 64 publications

(66 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has been reported that DRP-1, a key component of the mitochondrial fission machinery, is required for mitochondrial fragmentation and programmed cell death in non-β-cell and β-cell apoptosis (33). Our recent study demonstrated that dRP-1 mediates high glucose-induced pancreatic β-cell apoptosis (13). In addition, the fact that high glucose levels lead to ER stress in β-cells has been confirmed (5,34).…”

Section: Discussionsupporting

confidence: 59%

“…Our previous studies have demonstrated that high glucose levels increase dRP-1 expression and yield dRP-1-induced mitochondrial fission resulting in mitochondrial fragmentation and apoptosis in pancreatic β-cells, while the dRP-1 dominant-negative mutant impedes fission and apoptosis. However, whether dRP-1 is also implicated in ER stress-induced pancreatic β-cell apoptosis has not been investigated (13).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dynamin-related protein 1 is implicated in endoplasmic reticulum stress-induced pancreatic β-cell apoptosis

Peng

Men²,

Zhang³

et al. 2011

Int J Mol Med

Self Cite

View full text Add to dashboard Cite

Abstract. Pancreatic β-cell dysfunction is a critical component in the pathogenesis of diabetes. Endoplasmic reticulum (ER) stress is one of the factors that induces pancreatic β-cell dysfunction, but the underlying mechanisms have not been well elucidated. In this study, we report that a mitochondrial fission modulator, dynamin-related protein 1 (DRP-1), plays an important role in ER stress-induced β-cell apoptosis. Induction of dRP-1 expression significantly promoted ER stress-induced apoptosis in the dRP-1 WT (dRP-1 wildtype) inducible β-cell line, but not in the dRP-1 K38A (a dominant negative mutant of dRP-1) inducible β-cell line. We further demonstrated that the mitochondrial membrane potential decreased, and that cytochrome c release, caspase-3 activation and generation of reactive oxygen species (ROS) were enhanced by induction of dRP-1 WT, but prevented by dRP-1 K38A in pancreatic β-cells under ER stress conditions. These results indicate that dRP-1 mediates ER stress-induced pancreatic β-cell apoptosis.

show abstract

Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Dynamin-related protein 1 is implicated in endoplasmic reticulum stress-induced pancreatic β-cell apoptosis

Peng

Men²,

Zhang³

et al. 2011

Int J Mol Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent studies suggest that Drp1 recruitment involves posttranslational modifications including sumoylation, S-nitrosylation, ubiquitination, and phosphorylation (16,17). Interestingly, Drp1 activation under glucolipotoxic conditions in pancreatic b-cells leads to abnormalities in mitochondrial structure and function, followed by activation of proapoptotic signaling cascades (18)(19)(20)(21). It has recently been reported that manipulation of mitochondrial morphology by overexpressing dominantnegative Drp1 with erased GTPase activity decreases GSIS in INS-1E insulinoma cells, and this was attributed to increased mitochondrial proton leak (22).…”

mentioning

confidence: 99%

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

et al. 2017

View full text Add to dashboard Cite

In pancreatic b-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient b-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic b-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria.The development of type 2 diabetes is associated with mitochondrial dysfunction in pancreatic b-cells. b-Cells have developed highly coordinated mechanisms that link glucose sensing with metabolic signaling cascades that direct the secretion of sufficient insulin to maintain glucose homeostasis (1). The mechanism underlying glucose-stimulated insulin secretion (GSIS) from b-cells involves glucose uptake by specific glucose transporters followed by glucose catabolism through glycolysis yielding pyruvate, which in turn is further catabolized via the tricarboxylic acid cycle. Both glycolysis and tricarboxylic acid cycle turnover generate reducing power that is used by the mitochondrial respiratory chain to produce ATP through oxidative phosphorylation. The resultant increase in the cytosolic ATP/ADP ratio closes ATP-sensitive K + (K ATP ) channels, thus depolarizing the plasma membrane. Depolarization triggers opening of voltagegated Ca 2+ channels, and the influx of Ca 2+ ions consequently leads to exocytosis of insulin-containing granules from b-cells (2). This sequence of events illustrates that b-cell mitochondria exert strong control over GSIS (3), as mitochondrial energy-transducing processes dictate how fast and efficiently glucose is converted to ATP. Mitochondrial dysfunction impairs glucose-insulin secretion coupling and ultimately promotes b-cell apoptosis and death, one of the key features of type 2 diabetes (4).Mitochondria are dynamic organelles that are constantly remodeled through the opposing action of fission and fusion proteins (5). Until recently, the influence of mitochondrial dynamics over energy transduction has been underappreciated. The continuous changes in mitochondrial morphology are controlle...

show abstract

“…In a cultured b-cell model, high glucose concentrations induced apoptosis (114). Inhibiting mitochondrial fission prevented the high-glucose-induced b-cell apoptosis (114), suggesting that mitochondrial fission may regulate the circulating insulin levels by participating in pancreatic b-cell apoptosis in diabetes.…”

Section: Mitochondrial Dynamics In Pancreatic B-cells and Insulin Secmentioning

confidence: 99%

Mitochondrial Dynamics in Diabetes

Yoon

Galloway

Jhun

et al. 2011

Antioxidants & Redox Signaling

190

164

View full text Add to dashboard Cite

Mitochondria are at the center of cellular energy metabolism and regulate cell life and death. The cell biological aspect of mitochondria, especially mitochondrial dynamics, has drawn much attention through implications in human pathology, including neurological disorders and metabolic diseases. Mitochondrial fission and fusion are the main processes governing the morphological plasticity and are controlled by multiple factors, including mechanochemical enzymes and accessory proteins. Emerging evidence suggests that mitochondrial dynamics plays an important role in metabolism-secretion coupling in pancreatic b-cells as well as complications of diabetes. This review describes an overview of mechanistic and functional aspects of mitochondrial fission and fusion, and comments on the recent advances connecting mitochondrial dynamics with diabetes and diabetic complications. Antioxid. Redox Signal. 14, 439-457.

show abstract

Dynamin-related protein 1 mediates high glucose induced pancreatic beta cell apoptosis

Cited by 64 publications

References 34 publications

Dynamin-related protein 1 is implicated in endoplasmic reticulum stress-induced pancreatic β-cell apoptosis

Dynamin-related protein 1 is implicated in endoplasmic reticulum stress-induced pancreatic β-cell apoptosis

Direct Substrate Delivery Into Mitochondrial Fission–Deficient Pancreatic Islets Rescues Insulin Secretion

Mitochondrial Dynamics in Diabetes

Contact Info

Product

Resources

About