Free radical–induced megamitochondria formation and apoptosis

Karbowski, Mariusz; Kurono, Chieko; Woźniak, Michał; Ostrowski, Mariusz; Teranishi, Masaaki; Nishizawa, Yuji; Usukura, Jiro; Soji, Tśuyoshi; Wakabayashi, Takashi

doi:10.1016/s0891-5849(98)00209-3

Cited by 140 publications

(98 citation statements)

References 44 publications

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“…Marked increase in the percentage of oversized mitochondria with structural abnormalities have been reported in several instances including in RPE cells of advance aged individuals with Fig. 9 increasing severity [42] of AMD at the synaptic terminals of old rats [75] and in other adverse conditions where cells are exposed to large amounts of free radicals over an extended period [76,77]. The speculation is that numeric loss of mitochondria is due, in part, to impaired duplicative capacity of these organelles and that a shift in size compensates for numbers to keep volume density and area involved in cellular respiration constant during the lifespan of the individual [70,[78][79][80].…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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“…93 Therefore, to test the oxidative stress hypothesis, we treated cells with carboxy-H2-DCFDA, a fluorochrome that fluoresces in the presence of increased reactive oxygen species (ROS). 94 Pretreatment of Jurkat cells with either NA or NAM resulted in an increase in oxidative stress. Thus, a reduction in oxidative stress does not appear to be a major mechanism responsible for the decrease in constitutive levels of activated NF-kB.…”

Section: Discussionmentioning

confidence: 99%

The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

et al. 2000

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The bile salt, sodium deoxycholate (NaDOC), is a natural detergent that promotes digestion of fats. At high physiologic levels, NaDOC activates many stress-response pathways and induces apoptosis in various cell types. NaDOC induces DNA damage and activates poly(ADP-ribose) polymerase (PARP), an enzyme that utilizes NAD + as a substrate to repair DNA. NaDOC also induces oxidative stress, endoplasmic reticulum (ER) stress and contributes to protein malfolding. The NAD + precursors, nicotinic acid (NA) and nicotinamide (NAM) were found to protect cells against NaDOC-induced apoptosis. NA and NAM also decreased constitutive levels of both activated NF-kB and GRP78, two proteins that respond to oxidative stress. However, the mechanism by which NA and NAM protects cells against apoptosis does not involve a reduction in constitutive levels of oxidative stress. NA or NAM treatment increased the protein levels of glyceraldehyde-3-phosphate dehydrogense (GAPDH), a multi-functional enzyme, in the nucleus and cytoplasm, respectively. NAM did not activate the promoter/response elements of 13 stress response genes nor reduce intracellular non-protein thiols, suggesting that it is non-toxic to cells. NAM thus has promise as a dietary supplement to help prevent disorders involving excessive apoptosis. Cell Death and Differentiation (2000) 7, 314 ± 326.

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“…Both situations are considered to be adaptive processes at the subcellular level to unfavourable environments. For example, it has been demonstrated that when cells are exposed to excess amount of free radicals, the mitochondria become enlarged decreasing the rate of oxygen consumption and reducing ROS production [54]. These mechanisms are likely to play a role also in diabetes and in beta cell function.…”

Section: Discussionmentioning

confidence: 99%

Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients

et al. 2005

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Aims/hypothesis: Little information is available on the insulin release properties of pancreatic islets isolated from type 2 diabetic subjects. Since mitochondria represent the site where important metabolites that regulate insulin secretion are generated, we studied insulin release as well as mitochondrial function and morphology directly in pancreatic islets isolated from type 2 diabetic patients. Methods: Islets were prepared by collagenase digestion and density gradient purification, and insulin secretion in response to glucose and arginine was assessed by the batch incubation method. Adenine nucleotides, mitochondrial membrane potential, the expression of UCP-2, complex I and complex V of the respiratory chain, and nitrotyrosine levels were evaluated and correlated with insulin secretion. Results: Compared to control islets, diabetic islets showed reduced insulin secretion in response to glucose, and this defect was associated with lower ATP levels, a lower ATP/ADP ratio and impaired hyperpolarization of the mitochondrial membrane. Increased protein expression of UCP-2, complex I and complex V of the respiratory chain, and a higher level of nitrotyrosine were also found in type 2 diabetic islets. Morphology studies showed that control and diabetic beta cells had a similar number of mitochondria; however, mitochondrial density volume was significantly higher in type 2 diabetic beta cells. Conclusions/ interpretation: In pancreatic beta cells from type 2 diabetic subjects, the impaired secretory response to glucose is associated with a marked alteration of mitochondrial function and morphology. In particular, UCP-2 expression is increased (probably due to a condition of fuel overload), which leads to lower ATP, decreased ATP/ADP ratio, with consequent reduction of insulin release.

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Free radical–induced megamitochondria formation and apoptosis

Cited by 140 publications

References 44 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

The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients

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