AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells

Rita, Anthea Di; D’Acunzo, Pasquale; Simula, Luca; Campello, Silvia; Strappazzon, Flavie; Cecconi, Francesco

doi:10.3389/fncel.2018.00092

Cited by 66 publications

(37 citation statements)

References 32 publications

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“…Since oxidative stress is closely related with mitophagy [24], and mitophagy protects cells from apoptosis under environmental stress [25, 26]. We next explore whether high glucose inhibits RPE proliferation and promotes cell apoptosis by regulating oxidative stress mediated mitophagy.…”

Section: Resultsmentioning

confidence: 99%

High-glucose Induces Retinal Pigment Epithelium Mitochondrial Pathways of Apoptosis and Inhibits Mitophagy by Regulating ROS/PINK1/Parkin Signal Pathway

Yang¹,

Yuan

et al. 2018

Preprint

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Diabetic retinopathy (DR) caused visual performance degradation seriously endangers human beings’ health, uncovering the underlying mechanism might shed light on the discovery of DR therapeutic treatments. In this study, we found that the effects of glucose on retinal pigment epithelium (RPE) varies in a dose dependent manner, high-glucose promotes ROS generation and cell apoptosis, inhibits mitophagy as well as proliferative abilities, while low-glucose induces ROS production and cell mitophagy, but has little impacts on cell apoptosis and proliferation. Of note, the toxic effects of high-glucose on RPE are alleviated by ROS scavengers and aggravated by autophagy inhibitor 3-methyladenine (3-MA) or mitophagy inhibitor cyclosporin A (CsA). High-glucose induced ROS generation is merely eliminated by ROS scavengers instead of mitophagy or autophagy inhibitor. We also proved that high-glucose inhibits cell proliferation and promotes cell apoptosis by regulating ROS mediated inhibition of mitophagy. In addition, mitophagy associated proteins PINK1 and Parkin are downregulated by high-glucose or hydrogen peroxide treatments, which are reversed by ROS scavengers. Of note, Knock-down of PINK1 decreases phospharylated Parkin instead of total Parkin levels in RPE. Intriguingly, high-glucose’s inhibiting effects on cell mitophagy as well as proliferation and its promoting effects on cell apoptosis are reversed by either PINK1 or Parkin overexpression. Therefore, we concluded that high-glucose promotes RPE apoptosis and inhibits cell proliferation as well as mitophagy by regulating oxidative stress mediated inactivation of ROS/PINKl/Parkin signal pathway.

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Section: Resultsmentioning

confidence: 99%

High-glucose Induces Retinal Pigment Epithelium Mitochondrial Pathways of Apoptosis and Inhibits Mitophagy by Regulating ROS/PINK1/Parkin Signal Pathway

Yang¹,

Yuan

et al. 2018

Preprint

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“…Mitophagy is a quality control process: damaged, depolarized mitochondria are removed, thereby limiting the generation of reactive oxygen species (ROS) and release of apoptogenic factors and blocking cell death (e.g. Wang et al, 2017;Qiao et al, 2016;Yu et al, 2018b;Di Rita et al, 2018;Li et al, 2018). However, mitophagy is only beneficial to the cells if it occurs in a limited and regulated manner, and its over-activation can be lethal, as outlined below.…”

Section: Death From Over-eatingelimination Of Intracellular Organellementioning

confidence: 99%

Autophagy-dependent cell death – where, how and why a cell eats itself to death

Bialik

Dasari

Kimchi

2018

Journal of Cell Science

246

165

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Autophagy as a means of cell killing was first advanced by Clark's phenotypic description of 'Type II autophagic cell death' in 1990. However, this phenomenon later came into question, because the presence of autophagosomes in dying cells does not necessarily signify that autophagy is the cause of demise, but rather may reflect the efforts of the cell to prevent it. Resolution of this issue comes from a more careful definition of autophagy-dependent cell death (ADCD) as a regulated cell death that is shown experimentally to require different components of the autophagy machinery without involvement of alternative cell death pathways. Following these strict criteria, ADCD has been validated in both lower model organisms and mammalian cells, highlighting its importance for developmental and pathophysiological cell death. Recently, researchers have defined additional morphological criteria that characterize ADCD and begun to explore how the established, well-studied autophagy pathway is subverted from a survival to a death function. This Review explores validated models of ADCD and focuses on the current understanding of the mechanisms by which autophagy can kill a cell.

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“…Mitochondria are the main source of ROS within the cell and mitophagy is not only induced by oxidative stress but also plays a major role in modulating ROS in the cell 67,68 . More specifically, AMBRA1 mediated mitophagy plays an important role in counteracting oxidative stress in neuronal cells 69 . Our results suggest increased mitophagy induction (Bnip3 and Bnip3l) in Ambra1 +/+ animals) 7 days after ONC, whereas those levels are not increased in the Ambra1 +/gt animals.…”

Section: Discussionmentioning

confidence: 99%

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

et al. 2020

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Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d Ambra1 +/gt (autophagy/beclin-1 regulator 1 +/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+ , an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors.

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AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells

Cited by 66 publications

References 32 publications

High-glucose Induces Retinal Pigment Epithelium Mitochondrial Pathways of Apoptosis and Inhibits Mitophagy by Regulating ROS/PINK1/Parkin Signal Pathway

High-glucose Induces Retinal Pigment Epithelium Mitochondrial Pathways of Apoptosis and Inhibits Mitophagy by Regulating ROS/PINK1/Parkin Signal Pathway

Autophagy-dependent cell death – where, how and why a cell eats itself to death

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

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