Mitochondrial DNA Oxidative Damage Triggering Mitochondrial Dysfunction and Apoptosis in High Glucose-Induced HRECs

Xie, Liping; Zhu, Xiaobo; Hu, Yiqun; Li, Tao; Gao, Yi; Shi, Yu; Tang, Shibo

doi:10.1167/iovs.07-1364

Cited by 72 publications

(61 citation statements)

References 40 publications

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“…28 A recent finding highlighted how reactive oxygen species overproduction due to HG can increase damage to mitochondrial DNA, which can then further disrupt mitochondrial membrane potential and impair functioning of mitochondria. 10 Though these studies have reported on the effects of HG-induced oxidative stress on mitochondrial functioning, it is still unknown how HG conditions affect the morphology of mitochondria and how morphology changes may influence mitochondrial functioning and metabolic activity, culminating in apoptosis. Our work for the first time demonstrates how HG fragments mitochondria in retinal endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that HG induces apoptosis in the rat retinal endothelial cells (RRECs) 9 and recent studies have indicated that HG causes mitochondrial dysfunction through oxidative damage of mitochondrial DNA and contributes to apoptosis in the human retinal endothelial cells. 10 In various cell types, including rat hepato-cytes, myoblast, ventricular myocyte cells, bovine aortic endothelial cells, and mouse smooth muscle cells, exposure to HG has been shown to induce mitochondrial fragmentation but it is currently unknown whether mitochondrial morphology is affected by HG in the retinal endothelial cells and whether this impacts oxygen consumption rate, an index for mitochondrial metabolic activity. 7,8,11 Altered mitochondrial morphology has been associated with membrane potential heterogeneity 3 and increased oxidative stress in HG conditions.…”

mentioning

confidence: 99%

“…7,8,[11][12][13] A recent study indicated that HG decreases membrane potential and increases reactive oxygen species production. 10 Changes in mitochondrial morphology promote the opening of the mitochondrial permeability transition pore, a critical step that leads to reduced mitochondrial membrane potential and commits cells to apoptosis.…”

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confidence: 99%

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High Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells

Trudeau

Molina

Guo

et al. 2010

The American Journal of Pathology

120

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Mitochondrial dysfunction has been implicated in diabetic complications; however , it is unknown whether hyperglycemia affects mitochondrial morphology and metabolic capacity during development of diabetic retinopathy. We investigated high glucose (HG) effects on mitochondrial morphology, membrane potential heterogeneity, cellular oxygen consumption, extracellular acidification, cytochrome c release, and apoptosis in retinal endothelial cells. Diabetes is characterized by hyperglycemia and consequent functional failure of various target organs including the eye. In the working-age population, diabetic retinopathy is the leading cause of blindness, 1 which is triggered at least in part by hyperglycemia-induced apoptosis. While biochemical studies have implicated mitochondrial dysfunction as an underlying mechanism for inducing apoptosis, 2 the implications of mitochondrial structural changes in this process have only recently begun to be examined. In most cell types, mitochondria exist as long tubular networks that are precisely regulated by the rates of mitochondrial fusion and fission events. Disruption in this delicate balance induces altered mitochondrial membrane potential heterogeneity, 3-5 mitochondrial fragmentation, and apoptosis. 6 -8 Although oxidative stress is known to increase in diabetic retinas and trigger pro-apoptotic actions of mitochondria including the release of cytochrome c, it is currently unclear if compromised mitochondrial structure is a necessary event for high glucose (HG)-mediated apoptosis. We have shown that HG induces apoptosis in the rat retinal endothelial cells (RRECs) 9 and recent studies have indicated that HG causes mitochondrial dysfunction through oxidative damage of mitochondrial DNA and contributes to apoptosis in the human retinal endothelial cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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High Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells

Trudeau

Molina

Guo

et al. 2010

The American Journal of Pathology

120

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“…In human retinal vascular endothelial cells, incubation with high glucose induces an mtDNA oxidative damage, as well as a fall in the mitochondrial membrane potential (MMP), associated to an increase in ROS synthesis, and the presence of early apoptosis. Based on these data, the authors suggest that mtDNA oxidative damage, in the presence of high glucose, is the "trigger" of cell dysfunction (Xie et al, 2008). Evidence provided by Botto et al (1995) shows that mtDNA lesions are present in circulating cells and hearts of patients with coronary disease, supporting the relevance of mtDNA in the origin of atherosclerosis.…”

Section: Mitochondrial Deoxyribonucleic Acid (Mtdna)mentioning

confidence: 96%

“…In addition, in human retinal vascular endothelial cells, incubation with high glucose induces mtDNA oxidative damage, as well as a fall in the mitochondrial membrane potential (MMP), associated to an increase in ROS synthesis and the presence of early apoptosis (Xie et al, 2008). In their work, Bhatt et al (2013) showed that human umbilical endothelial cells incubated with high glucose had a higher synthesis of ROS, a decrease of MMP, and endothelial apoptosis.…”

Section: Perspectivementioning

confidence: 99%

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

Alvarado-Vásquez¹

2015

Experimental Gerontology

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Time‐course effect of high‐glucose‐induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells

Al‐Κafaji

Sabry

Skrypnyk

2015

Cell Biology International

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The present study investigated the time-course effect of high-glucose-induced reactive oxygen species (ROS) on mitochondrial biogenesis and function in human renal mesangial cells and the effect of direct inhibition of ROS on mitochondria. The cells were cultured for 1, 4, and 7 days in normal glucose or high glucose in the presence and absence of Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) or catalase. Mitochondrial ROS production was assessed by confocal microscope. mtDNA copy number and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factors 1 (NRF-1), and mitochondrial transcription factor A (TFAM) transcripts were analyzed by real-time PCR. PGC-1α, NRF-1, and TFAM proteins were analyzed by Western blotting. Mitochondrial function was determined by assessing mitochondrial membrane potential and adenosine triphosphate (ATP) levels. High glucose induced significant increases in mitochondrial superoxide and hydrogen peroxide (H2 O2 ) at day 1, which remained significantly elevated at days 4 and 7. The copy number of mtDNA and expression of PGC-1α, NRF-1, and TFAM were significantly increased at 1 day in high glucose but were significantly decreased at 4 and 7 days. A progressive decrease in mitochondrial membrane potential was observed at 1, 4, and 7 days in high glucose, and this was associated with decreased ATP levels. Treatment of cells with MnTBAP or catalase during high-glucose incubation attenuated ROS production and reversed the alterations in mitochondrial biogenesis and function. Increased mitochondrial biogenesis in human renal mesangial cells may be an early adaptive response to high-glucose-induced ROS, and prolonged ROS production induced by chronic high glucose decreased mitochondrial biogenesis and impaired mitochondrial function. Protection of mitochondria from high-glucose-induced ROS may provide a potential approach to retard the development and progression of diabetic nephropathy.

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Mitochondrial DNA Oxidative Damage Triggering Mitochondrial Dysfunction and Apoptosis in High Glucose-Induced HRECs

Abstract: 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.

Cited by 72 publications

References 40 publications

High Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells

High Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

Time‐course effect of high‐glucose‐induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells

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