Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species

Tianzheng Yu, Shey Shing Sheu, James L. Robotham, Yisang Yoon

Research output: Contribution to journalArticle

287 Scopus citations

Abstract

Aims: One of the main causes of cardiovascular complications in diabetes is the hyperglycaemia-induced cell injury, and mitochondrial fission has been implicated in the apoptotic process. We investigated the role of mitochondrial fission in high glucose-induced cardiovascular cell injury. Methods and results: We used several types of cultured mouse, rat, and bovine cells from the cardiovascular system, and evaluated mitochondrial morphology, reactive oxygen species (ROS) levels, and apoptotic parameters in sustained high glucose incubation. Adenoviral infection was used for the inhibition of the fission protein DLP1. We found that mitochondria were short and fragmented in cells incubated in sustained high glucose conditions. Under the same conditions, cellular ROS levels were high and cell death was increased. We demonstrated that the increased level of ROS causes mitochondrial permeability transition (MPT), phosphatidylserine exposure, cytochrome c release, and caspase activation in prolonged high glucose conditions. Importantly, maintaining tubular mitochondria by inhibiting mitochondrial fission in sustained high glucose conditions normalized cellular ROS levels and prevented the MPT and subsequent cell death. These results demonstrate that mitochondrial fragmentation is an upstream factor for ROS overproduction and cell death in prolonged high glucose conditions. Conclusion: These findings indicate that the fission-mediated fragmentation of mitochondrial tubules is causally associated with enhanced production of mitochondrial ROS and cardiovascular cell injury in hyperglycaemic conditions.

Original languageEnglish (US)
Pages (from-to)341-351
Number of pages11
JournalCardiovascular Research
Volume79
Issue number2
DOIs
StatePublished - Jul 1 2008

Keywords

  • Apoptosis
  • DLP1
  • Drp1
  • Hyperglycaemia
  • Mitochondria
  • Mitochondrial fission
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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