Resveratrol-induced mitochondrial dysfunction and apoptosis are associated with Ca2+ and mCICR-mediated MPT activation in HepG2 cells

Ma, Xiaodong; Tian, Xue-Mei; Huang, Xingxu; Yan, Fang; Qiao, Dongfang

doi:10.1007/s11010-007-9431-8

Cited by 56 publications

(39 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytochrome c release Release of cytochrome c, a putative event of the mitochondria apoptotic pathway following loss of Δψm, was measured as described [52,53]. After H 2 O 2 treatment, the cells were washed in PBS, resuspended in 1 ml of mitochondrial medium containing 250 mM sucrose, 10 mM KCl, 20 mM HEPES-KOH, pH 7.5, 1 mM EGTA, 1 mM EDTA, 1.5 mM MgCl 2 , and 1% protease inhibitors mixture.…”

Section: Culture and Characterization Of Primary Human Rpe Cellsmentioning

confidence: 99%

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

Burke

et al. 2010

j ocul biol dis inform

View full text Add to dashboard Cite

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.

show abstract

Section: Culture and Characterization Of Primary Human Rpe Cellsmentioning

confidence: 99%

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

Burke

et al. 2010

j ocul biol dis inform

View full text Add to dashboard Cite

show abstract

“…Calcium signaling pathways are necessary for the motility and invasive characteristics of malignant tumors, as it controls cell restructuring and dedifferentiation [54]. Another potential mechanism of action for resveratrol targets the excessive energy demand of tumor cells, lowers calcium thresholds, and prolongs intracellular calcium surges, all of which ultimately lead to cell death as a result of mitochondrial dysfunction [55]. Previously, resveratrol has been shown to suppress CD4 + CD25 + regulatory T cells (T reg cells) in a preclinical cancer model [56].…”

Section: Medical Relevance Of Modulation Of Cellular Calcium Signamentioning

confidence: 99%

“…Mitochondria are critical initiators of apoptotic pathways via calcium signaling. Resveratrol has been shown to induce mitochondrial apoptosis by alteration of the mitochondrial membrane potential and eliciting a mitochondrial permeability transition (MPT) pore by lowering the calcium threshold necessary for MPT opening [27,55,76]. This mechanism is currently intensively investigated as a potential for anti-cancer drug therapy [77,78].…”

Section: Therapeutic Potential Of Resveratrol Via the Modulation Omentioning

confidence: 99%

Resveratrol and Calcium Signaling: Molecular Mechanisms and Clinical Relevance

et al. 2014

View full text Add to dashboard Cite

Resveratrol is a naturally occurring compound contributing to cellular defense mechanisms in plants. Its use as a nutritional component and/or supplement in a number of diseases, disorders, and syndromes such as chronic diseases of the central nervous system, cancer, inflammatory diseases, diabetes, and cardiovascular diseases has prompted great interest in the underlying molecular mechanisms of action. The present review focuses on resveratrol, specifically its isomer trans-resveratrol, and its effects on intracellular calcium signaling mechanisms. As resveratrol's mechanisms of action are likely pleiotropic, its effects and interactions with key signaling proteins controlling cellular calcium homeostasis are reviewed and discussed. The clinical relevance of resveratrol's actions on excitable cells, transformed or cancer cells, immune cells and retinal pigment epithelial cells are contrasted with a review of the molecular mechanisms affecting calcium signaling proteins on the plasma membrane, cytoplasm, endoplasmic reticulum, and mitochondria. The present review emphasizes the correlation between molecular mechanisms of action that have recently been identified for resveratrol and their clinical implications.

show abstract

“…Moreover, resveratrol has also been shown to stimulate expression of genes for oxidative phosphorylation and mitochondrial biogenesis, which is accompanied with its protective effects against metabolic disease in animal models [66]. Other studies, on the other hand, show that resveratrol and its derivatives can activate the mitochondrial apoptotic pathway in vitro in transformed human cells and in vivo in cancer animal models [67][68][69]. When applied by peritumor injection, resveratrol leads to a decrease of mitochondrial membrane potential in tumor cells [69].…”

Section: Environment Factors That Act On Mitochondriamentioning

confidence: 99%

Picturing Molecular Environmental Health From Mitochondria

Zhou¹

2013

Health Care: Current Reviews

View full text Add to dashboard Cite

triphosphate IntroductionHuman diseases are determined by both genetic and environmental risk factors. A recent investigation indicates that environmental factors contribute to about 80% of the 102 diseases and injuries listed by the World Health Organization (WHO) for the year 2002, and account for 24% of the global burden of disease [1]. These data clearly indicate a key role of environmental factors in human health. Modern molecular and cellular studies have revealed a great detail of normal and disease biological processes at the molecular level; however, the molecular mechanisms by which environmental risk factors cause human diseases are still not well understood. An in-depth understanding of these molecular mechanisms is the prerequisite for the design of new strategies of prevention and therapy, and requires intensive investigations in the cutting edge field -Molecular Environmental Health. In this essay, the author uses the organelle mitochondria as an example to connect Molecular Biology and Environmental Health from available literature, to demonstrate the level of clarity of scientific understanding we can achieve by studying environmental health at the molecular and cellular levels. Recent Advances in Mitochondrial BiologyAs an important cellular organelle, mitochondria are known for producing adenosine triphosphate (ATP), buffering calcium and participating apoptosis. Moreover, mitochondria host a variety of metabolic processes, such as the tricarboxylic acid (TCA) cycle, fatty acid beta-oxidation, and synthesis of lipid, steroid, heme and ironsulfur clusters. In the past decades, several significant progresses have been made which have expanded our conventional understanding of the function and regulation of mitochondria.One progress is that mitochondria modulate cellular signal pathways by generating reactive oxygen species (ROS). ROS are oxygencontaining, highly chemically reactive molecules, including superoxide anion, hydroxyl radical and hydrogen peroxide. Mitochondria generate superoxide from oxygen at the site of the mitochondrial electron transport chain as an intrinsic product of oxidative phosphorylation. Traditionally, ROS are considered toxic as high level of ROS causes oxidative damage: protein oxidation, lipid peroxidation and DNA mutation. However, numerous studies have demonstrated that moderate or low levels of ROS are an important cellular signaling transducer in cell proliferation, differentiation and migration [2][3][4][5][6]. In fact, mitochondria-generated superoxide is converted to hydrogen peroxide. Hydrogen peroxide is a signaling messenger that can travel for a distance within the cell to oxidize key protein residues such as cysteines, resulting in change of the conformation or activity of kinases, phosphatases or transcription factors in various cellular signaling pathways. These redox-sensitive signaling pathways, such as the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/Erk), nuclear factor erythroid-derived 2-related factor 2 (Nrf-2), c...

show abstract

Resveratrol-induced mitochondrial dysfunction and apoptosis are associated with Ca2+ and mCICR-mediated MPT activation in HepG2 cells

Cited by 56 publications

References 33 publications

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

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

Resveratrol and Calcium Signaling: Molecular Mechanisms and Clinical Relevance

Picturing Molecular Environmental Health From Mitochondria

Contact Info

Product

Resources

About