Mitochondrial DNA oxidative damage triggering mitochondrial dysfunction and apoptosis in high glucose-induced HRECs

Lin Xie, Xiaobo Zhu, Yiqun Hu, Tao Li, Yi Gao, Yu Shi, Shibo Tang
Investigative Ophthalmology & Visual Science 2008, 49 (9): 4203-9

PURPOSE: Oxidative stress is linked to early apoptosis in diabetic retinopathy, and reactive oxygen species (ROS) play a critical role in that stress. Endogenous ROS generated from attacks of mitochondria on nearby mitochondrial DNA (mtDNA) could lead to constant ROS overproduction. The authors explored the role of mtDNA oxidative damage in high glucose-induced dysfunction in human retinal vascular endothelial cells (HRECs).

METHODS: mtDNA oxidative damage was examined by Southern blot analysis in HRECs treated with high glucose. The effect of mtDNA damage on the mRNA expression of respiratory chain subunits, change of mitochondrial membrane potential (Deltapsi(m)), overproduction of ROS, and apoptosis were assessed in high glucose-treated HRECs by RT-PCR, flow cytometry, and confocal microscopy.

RESULTS: mtDNA oxidative damage increased rapidly after short-term (3-hour) exposure to high glucose (30 mM) and was severe after 48-hour exposure. Accordingly, the mRNA level of respiratory chain subunits NADPH-1 and CO1 encoded by mtDNA was significantly downregulated after 6-hour exposure to high glucose (P < 0.05) compared with levels encoded by nuclear DNA. Treatment with 12-, 24-, and 48-hour high glucose resulted in decreased membrane potential and overproduction of ROS in HRECs (P < 0.05); early apoptosis was observed with 24-hour (9.63% +/- 1.26%) and 48-hour (12.30% +/- 1.43%) treatment.

CONCLUSIONS: mtDNA oxidative damage seems to be the "trigger" for cell dysfunction in high glucose-treated HRECs by setting in motion the vicious circle of mtDNA damage leading to ROS overproduction and further mtDNA damage, which may explain in part early vascular damage in diabetic retinopathy.

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