Mitochondrial Complex I Defect Induces ROS Release and Degeneration in Trabecular Meshwork Cells of POAG Patients: Protection by Antioxidants

He, Yuan; Leung, Ka Nang; Zhang, Yue Hong; Duan, Shan; Zhong, Xiaojing; Jiang, Ru; Zhan, Ping; Tombran-Tink, Joyce; Ge, Junbo

doi:10.1167/iovs.07-1361

Cited by 136 publications

(113 citation statements)

References 52 publications

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“…The profound decline in complex I activity occurring after CS/Tx is significant because complex I has been shown to be a major source of ROS in many diseases [17][18][19]. In addition, complex III, which was also inactivated after CS/Tx, also participates in ROS generation [20][21][22].…”

Section: Resultsmentioning

confidence: 99%

Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation

Shrum

Parajuli

2016

J Kidney

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Long-term renal function is compromised in patients receiving deceased donor kidneys which require cold storage exposure prior to transplantation. It is well established that extended cold storage induces renal damage and several labs, including our own, have demonstrated renal mitochondrial damage after cold storage alone. However, to our knowledge, few studies have assessed renal and mitochondrial function after transplantation of rat kidneys exposed to short-term (4 hr) cold storage compared to transplant without cold storage (autotransplantation). Our data reveal that cold storage plus transplantation exacerbated renal and mitochondrial dysfunction when compared to autotransplantation alone.Citation: Shrum S, MacMillan-Crow LA, Parajuli N (2016) Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation.

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Section: Resultsmentioning

confidence: 99%

Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation

Shrum

Parajuli

2016

J Kidney

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“…ATP levels ATP levels were determined using a luciferin/ luciferase-based assay as described [56]. Cells from confluent RPE cultures were harvested and 1×10 5 cells from each sample in an age group seeded into wells of a 96-well plate in SFM for 24 h. Culture medium was then removed, cell membranes permeabilized using 50 μl of somatic cell ATP-releasing reagent, and samples incubated with 50 μl ATPAssay Mix Reagent containing luciferin and luciferase.…”

Section: Age-related Changes In Mitochondrial Functionmentioning

confidence: 99%

“…Mitochondrial membrane potential Mitochondrial membrane potential (Δψm) measurements were carried out as we have described [56] using the indicator JC-1, a lipophilic, and cationic dye which fluoresces red when it aggregates in the matrix of healthy, high-potential mitochondria, and green in cells with low ΔΨm. Cells from confluent RPE cultures were harvested and JC-1 (1 μg/ml) added to 2×10 6 cells/ml in suspension.…”

Section: Age-related Changes In Mitochondrial Functionmentioning

confidence: 99%

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Burke

et al. 2010

j ocul biol dis inform

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Impairment of mitochondria function and cellular antioxidant systems are linked to aging and neurodegenerative diseases. In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment that contributes to age-related visual dysfunction. Here, we examined changes in mitochondrial function in human RPE cells and sensitivity to oxidative stress with increased chronological age. Primary RPE cells from young (9-20)-, mid-age (48-60)-, and >60 (62-76)-year-old donors were grown to confluency and examined by electron microscopy and flow cytometry using several mitochondrial functional assessment tools. Susceptibility of RPE cells to H 2 O 2 toxicity was determined by lactate dehydrogenase and cytochrome c release, as well as propidium iodide staining. Reactive oxygen species, cytoplasmic Ca 2+ [Ca 2+ ] c , and mitochondrial Ca 2+ [Ca 2+ ] m levels were measured using 2′,7′-dichlorodihydrofluorescein diacetate, fluo-3/AM, and Rhod-2/AM, respectively, adenosine triphosphate (ATP) levels were measured by a luciferin/luciferase-based assay and mitochondrial membrane potential (ΔΨm) estimated using 5,5′,6,6′-tetrachloro 1,1′3,3′-tetraethylbenzimid azolocarbocyanine iodide. Expression of mitochondrial and antioxidant genes was determined by real-time polymerase chain reaction. RPE cells show greater sensitivity to oxidative stress, reduction in expression of mitochondrial heat shock protein 70, uncoupling protein 2, and superoxide dismutase 3, and greater expression of superoxide dismutase 2 levels with increased chronological age. Changes in mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity were more prominent in samples obtained from >60 years old compared to midage and younger donors. These mitochondria abnormalities correlated with lower ATP levels, reduced ΔΨm, decreased [Ca 2+ ] c , and increased sequestration of [Ca 2+ ] m in cells with advanced aging. Our study provides evidence for mitochondrial decay, bioenergetic deficiency, weakened antioxidant defenses, and increased sensitivity of RPE cells to oxidative stress with advanced aging. Our findings suggest that with increased severity of mitochondrial decay and oxidative stress, RPE function may be altered in some individuals in a way that makes the retina more susceptible to age-related injury.

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“…Interestingly, we have found mitochondrial dysfunction with electron transport chain complex I deficiency in skeletal muscle of TR4 Ϫ/Ϫ mice (Liu S, Lee, YF, Chou S, Uno H, Li G, Brookes P, Massett MP, Wu Q, Chen LM, and Chang C, unpublished observations). It has been reported that a complex I defect induces ROS release in primary open-angle glaucoma patients (16). Is it possible that the complex I defect accounts for the increased oxidative stress in TR4 Ϫ/Ϫ mice and finally leads to premature aging?…”

Section: Discussionmentioning

confidence: 99%

Premature aging with impaired oxidative stress defense in mice lacking TR4

Lee

Liu

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 ( TR4−/−) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4−/− mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4−/− MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4−/− MEFs, which further supports the hypothesis that the premature aging in TR4−/− mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.

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Mitochondrial Complex I Defect Induces ROS Release and Degeneration in Trabecular Meshwork Cells of POAG Patients: Protection by Antioxidants

Abstract: The authors propose that a mitochondrial complex I defect is associated with the degeneration of TM cells in patients with POAG, and antioxidants and MPT inhibitors can reduce the progression of this condition.

Cited by 136 publications

References 52 publications

Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation

Cold Storage Exacerbates Renal and Mitochondrial Dysfunction Following Transplantation

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Premature aging with impaired oxidative stress defense in mice lacking TR4

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