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Involvement of dynamin-related protein 1 in free fatty acid-induced INS-1-derived cell apoptosis

Liang Peng1, Xiuli Men, Wenjian Zhang

  • 1Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.

Plos One
|November 21, 2012
PubMed

Insights

Free fatty acids induce pancreatic beta cell apoptosis, a process linked to type 2 diabetes. This study shows Dynamin-related protein 1 (DRP-1) mediates this apoptosis, suggesting DRP-1 suppression as a therapeutic target.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Metabolic Diseases

Background:

  • Elevated free fatty acids (FFAs) contribute to type 2 diabetes mellitus (T2D) by inducing pancreatic beta cell apoptosis.
  • Mitochondrial dysfunction is implicated in FFA-induced beta cell apoptosis, but the precise molecular mechanisms remain unclear.
  • Dynamin-related protein 1 (DRP-1), a key regulator of mitochondrial fission, is investigated for its role in this process.

Purpose of the Study:

  • To elucidate the role of Dynamin-related protein 1 (DRP-1) in free fatty acid (FFA)-induced apoptosis of INS-1 beta cells.
  • To investigate whether DRP-1 mediates mitochondrial dysfunction and subsequent apoptosis in the context of T2D pathogenesis.
  • To assess the therapeutic potential of targeting DRP-1 for beta cell protection.

Main Methods:

  • Investigated DRP-1 expression and its impact on INS-1 cell apoptosis in vitro following FFA stimulation.
  • Utilized DRP-1 wild-type (WT) and dominant-negative mutant (K38A) INS-1-derived cell lines.
  • Validated findings in vivo using xenograft models in streptozotocin-treated diabetic mice, assessing apoptosis and mitochondrial parameters.

Main Results:

  • DRP-1 protein was upregulated in INS-1 cells and rat islets upon FFA stimulation, correlating with increased apoptosis.
  • Overexpression of DRP-1 exacerbated FFA-induced apoptosis, while dominant-negative DRP-1 (K38A) significantly protected against it, both in vitro and in vivo.
  • FFA-induced apoptosis was associated with decreased mitochondrial membrane potential, increased cytochrome c release, caspase-3 activation, and reactive oxygen species (ROS) generation, effects modulated by DRP-1 activity.

Conclusions:

  • DRP-1 plays a critical role in mediating FFA-induced pancreatic beta cell apoptosis.
  • DRP-1-induced mitochondrial dysfunction is a key mechanism linking FFAs to beta cell death in T2D.
  • Suppression of DRP-1 activity represents a potential therapeutic strategy to protect beta cells and combat T2D.

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