Increased mitochondrial fission is critical for hypoxia-induced pancreatic beta cell death.

Da Zhang,Yanfang Liu,Rui Li,Zhenyu Ti,Yao Tang,Xiaofeng Wang,Jigang Bai,Weidong Gao,Yi Lv,Zhichao Li,Hemachandra Reddy

doi:10.1371/journal.pone.0197266

Abstract

Hypoxia-mediated pancreatic beta cell death is one of the main causes of pancreatic beta celldeath, which leads to the loss of functional pancreatic beta cell mass and type 1 diabetes andtype 2 diabetes.However, the molecular mechanisms that control life and death of pancreatic beta cells remain poorly understood. Here we showed that mitochondrial fission was strongly induced in pancreatic beta cellsmainly due to an elevation of DRP1S616 phosphorylation through HIF-1αactivation and subsequent DRP1 mitochondrial translocation. Hypoxia-induced pancreatic beta cell death can be reversed by the inhibition of mitochondrial fission viaDRP1 knockdown. We further demonstrated that hypoxia-induced mitochondrial fission untightened the cristae formation, which subsequently triggers mitochondrial cytochrome c release and consequent caspase activation. Moreover, treatment with mitochondrial division inhibitor-1 (Mdivi-1), a specific inhibitor of DRP1-mediated mitochondrial fission, significantly suppressedbeta cell death in vitro, indicating a promising therapeutic strategy for treatment of diabetes.Taken together, our results reveal a crucial role for the DRP1-mediated mitochondrial fission in hypoxia-induced beta cell death, which provides a strong evidence for thisprocess as drug target indiabetestreatment.

Highlights

A fundamental challenge in treating diabetes is theidentification of the molecular basesthat cause beta cell failure in response to environmental stress factors, including hypoxia
Hypoxiainduces mitochondrial fragmentation in pancreatic beta cells To investigate the impact of hypoxia on the mitochondrial dynamics in pancreatic beta cells, the alterations of mitochondrial morphologywere examined by staining with mitochondrial dye,MitoTracker Green.Fluorescence microscopy analysis showed that hypoxia(1% or 3% O2) treatment resulted in a dramatic increase of mitochondrial fragmentationin pancreatic beta INS-1Ecells, with a higher increase at 1% O2 than at 3% O2of mitochondrial, indicating adosedependent manner (Fig 1A and 1B).Transmission electronmicroscopy (TEM)further revealed a significantly lower average mitochondrial lengthin pancreatic beta INS-1Ecells with hypoxia (1% or 3% O2) treatment compared with those under normoxia (Fig 1C and 1D)
HIF-1α activation and subsequently dynamin-related protein 1 (DRP1)(S616) phosphorylationis involved in hypoxia-induced mitochondrial fragmentation in pancreatic beta cells

Summary

Introduction

A fundamental challenge in treating diabetes is theidentification of the molecular basesthat cause beta cell failure in response to environmental stress factors, including hypoxia. More and more studies support that pancreatic betacells are heavily dependenton mitochondrial respiration and commonly sensitive to hypoxic stress due to their high consumption of oxygen during insulin secretion[1, 2].Hypoxia-mediated cell death is still one of the main problems that must be solved for transplantation to be regarded as a reliable therapy [3].the molecular mechanisms behind this are poorly understood. Mitochondria are multifunctional and highly dynamic organelles, which are regulated by constant fusion and fission events[4].

Methods

Results

Conclusion