Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 25, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn104
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Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species
1 Departments 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
* To whom correspondence should be sent: Yisang Yoon, Ph.D. 601 Elmwood Ave, Box 604 Rochester, NY 14642 TEL: (585) 275-3856 FAX: (585) 244-7271 E-mail: yisang_yoon{at}urmc.rochester.edu
Aims: One of the main causes of cardiovascular complications in diabetes is the hyperglycemia-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: 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.
Results: 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 hyperglycemic conditions.
Time for primary review: 21 days
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