Moderately Reduced ATP Levels Promote Oxidative Stress and Debilitate Autophagic and Phagocytic Capacities in Human RPE Cells

Schütt, F.; Aretz, Sebastian; Auffarth, Gerd U.; Kopitz, Jürgen

doi:10.1167/iovs.12-9845

Cited by 77 publications

(42 citation statements)

References 43 publications

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“…The levels in MSCs deficient in autophagic proteins, LC3B and BECN1, were 40-60% that of WT ATP levels. This decrease in ATP was not enough to cause cell death, as ATP levels need to drop significantly lower than 50% to cause cell death (40). However, when a stressor, such as H 2 O 2 , was added to the MSCs deficient in autophagic proteins, ATP levels further plummeted and caused cell death.…”

Section: Discussionmentioning

confidence: 99%

“…There are several explanations for the relationship between autophagy and ATP. The first is that depletion of ATP might also be due to inhibition of ATP synthesis (40). For example, retinal pigment epithelium cells from aged donors have lower levels of autophagy than their younger controls, and there is a decline in the activity of enzymes involved in ATP synthesis in these cells (40).…”

Section: Discussionmentioning

confidence: 99%

“…The first is that depletion of ATP might also be due to inhibition of ATP synthesis (40). For example, retinal pigment epithelium cells from aged donors have lower levels of autophagy than their younger controls, and there is a decline in the activity of enzymes involved in ATP synthesis in these cells (40). Another possibility is that autophagic degradation of mitochondria, other organelles, and proteins can yield significant substrate to provide energy to cells (43).…”

Section: Discussionmentioning

confidence: 99%

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Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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Oxidative stress resulting from inflammatory responses that occur during acute lung injury and sepsis can initiate changes in mitochondrial function. Autophagy regulates cellular processes in the setting of acute lung injury, sepsis, and oxidative stress by modulating the immune response and facilitating turnover of damaged cellular components. We have shown that mesenchymal stromal cells (MSCs) improve survival in murine models of sepsis by also regulating the immune response. However, the effect of autophagy on MSCs and MSC mitochondrial function during oxidative stress is unknown. This study investigated the effect of depletion of autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) and beclin 1 (BECN1) on the response of MSCs to oxidative stress. MSCs were isolated from wild-type (WT) and LC3B 2/2 or Becn1 1/2 mice. MSCs from the LC3B 2/2 and Becn1 1/2 animals had increased susceptibility to oxidative stress-induced cell death as compared with WT MSCs. The MSCs depleted of autophagic proteins also had impaired mitochondrial function (decreased intracellular ATP, reduced mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production) under oxidative stress as compared with WT MSCs. In WT MSCs, carbon monoxide (CO) preconditioning enhanced autophagy and mitophagy, and rescued the cells from oxidative stress-induced death. CO preconditioning was not able to rescue the decreased survival of MSCs from the LC3B 2/2 and Becn1 1/2 animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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“…The ATP level correlates positively with cell proliferation and negatively with the mitochondrial generation of ROS. Thus the ADP/ ATP ratio is an appropriate marker to differentiate cell viability and cell death (Schütt et al 2012;Shahraki et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells

2014

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Hyperglycemia plays an important role in the development of diabetic neuropathy. In this study, we investigated the protective effects of alpha lipoic acid (ALA) against high glucose-induced neurotoxicity in PC12 cells as a suitable in vitro model for studying neuronal functions. PC12 cells were treated with high glucose (25 mg/ml for 24 h) in the absence and presence of ALA (100 μM for 24 h). The viability of PC12 cells was estimated by using MTT assay. The expression of pro- apoptotic Bax, anti- apoptotic Bcl-2 and caspase 3 protein were evaluated by western blotting. The reactive oxygen species (ROS) levels were determined with 2,7-dichlorodihydro- fluorescein diacetate (H2DCFDA). Biochemical markers of oxidative stress were assessed by using the total antioxidant power (TAP), lipid peroxidation (LPO), ADP/ATP ratio, activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Pretreatment of PC12 cells with ALA, significantly improved high glucose-induced toxicity by increasing activity of antioxidant enzymes CAT and SOD in the PC12 cell. It also increased the concentrations of TAP. An elevated level of cell death and ROS in high glucose conditions, diminished with ALA treatment. Over expression of Bax and caspase 3 protein, elevation of ADP/ATP ratio and LPO level in high glucose- treated PC12 cells, were significantly reduced by ALA. It was concluded that ALA attenuates neurotoxicity induced by high glucose in PC12 cells.

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“…The decreased protein degradation was followed using autoradiography in the presence of autophagic inhibitors, further confirming an essential role for this degradative process in RPE health (Bergmann et al, 2004). The aging RPE is also associated with decreased ATP levels, suggested by some to contribute to reduced autophagy and POS uptake (Schutt et al, 2013; Schutt et al, 2012). Drusen in AMD donor eyes contains autophagic proteins and markers of exosomes, which are also found in the Bruch’s membrane (BM) of aged mice (Wang et al, 2009a; Wang et al, 2009b).…”

Section: Rpe and Photoreceptorsmentioning

confidence: 99%

Autophagy in the eye: Implications for ocular cell health

Frost

Mitchell

Boesze‐Battaglia

2014

Experimental Eye Research

120

108

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Autophagy, a catabolic process by which a cell “eats” itself, turning over its own cellular constituents, plays a key role in cellular homeostasis. In an effort to maintain normal cellular function, autophagy is often up-regulated in response to environmental stresses and excessive organelle damage to facilitate aggregated protein removal. In the eye, virtually all cell types from those comprising the cornea in the front of the eye to the retinal pigment epithelium (RPE) providing a protective barrier for the retina at the back of the eye, rely on one or more aspects of autophagy to maintain structure and/or normal physiological function. In the lens autophagy plays a critical role in lens fiber cell maturation and the formation of the organelle free zone. Numerous studies delineating the role of Atg5, Vsp34 as well as FYCO1 in maintenance of lens transparency are discussed. Corneal endothelial dystrophies are also characterized as having elevated levels of autophagic proteins. Therefore, novel modulators of autophagy such as lithium and melatonin are proposed as new therapeutic strategies for this group of dystrophies. In addition, we summarize how corneal Herpes Simplex Virus (HSV-1) infection subverts the cornea’s response to infection by inhibiting the normal autophagic response. Using glaucoma models we analyze the relative contribution of autophagy to cell death and cell survival. The cytoprotective role of autophagy is further discussed in an analysis of photoreceptor cell heath and function. We focus our analysis on the current understanding of autophagy in photoreceptor and RPE health, specifically on the diverse role of autophagy in rods and cones as well as its protective role in light induced degeneration. Lastly, in the RPE we highlight hybrid phagocytosis-autophagy pathways. This comprehensive review allows us to speculate on how alterations in various stages of autophagy contribute to glaucoma and retinal degenerations.

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Moderately Reduced ATP Levels Promote Oxidative Stress and Debilitate Autophagic and Phagocytic Capacities in Human RPE Cells

Abstract: Moderately decreased ATP levels such as seen in aged individuals might contribute to the vulnerability of RPE to oxidative stress damage and to dysfunction.

Cited by 77 publications

References 43 publications

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells

Autophagy in the eye: Implications for ocular cell health

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