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Cardiovascular Research Advance Access first published online on April 25, 2008
This version [Corrected Proof] published online on May 12, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn104
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

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

Tianzheng Yu1,3, Shey-Shing Sheu1,2,3, James L. Robotham1,2,3 and Yisang Yoon1,2,3,*

1 Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
2 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
3 Mitochondrial Research and Innovation Group, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA

* Corresponding author. Tel: +1 585 275 3856; fax: +1 585 244 7271. E-mail address: yisang_yoon{at}urmc.rochester.edu

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.

KEYWORDS Mitochondria; Mitochondrial fission; DLP1; Drp1; Hyperglycaemia; Apoptosis; Reactive oxygen species

Time for primary review: 21 days


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