Role of the autophagic‐lysosomal system on low potassium‐induced apoptosis in cultured cerebellar granule cells

Canu, Nadia; Tufi, Roberta; Serafino, Annalucia; Amadoro, Giuseppina; Ciotti, Maria Teresa; Calissano, Pietro

doi:10.1111/j.1471-4159.2004.02956.x

Cited by 122 publications

(112 citation statements)

References 73 publications

(177 reference statements)

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“…CQ treatment resulted in increased LC3-II levels as early as 6 h after addition and then continued to increase over a 24-h period. Inhibition of Beclin1 expression by siRNA knockdown or 3-methyladenine inhibition of VPS34 has been previously shown to inhibit AV production (1,30). Western blot analysis revealed a significant increase in Beclin1 levels at 12 and 24 h after CQ treatment, suggesting AV induction (Fig.…”

Section: Lysosome Dysfunction and Cell Starvation Induce An Increasementioning

confidence: 90%

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Walls

Ghosh

Franklin

et al. 2010

Journal of Biological Chemistry

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Macroautophagy (autophagy) is a process wherein bulk cytosolic proteins and damaged organelles are sequestered and degraded via the lysosome. Alterations in autophagy-associated proteins have been shown to cause neural tube closure defects, neurodegeneration, and tumor formation. Normal lysosome function is critical for autophagy completion and when altered may lead to an accumulation of autophagic vacuoles (AVs) and caspase activation. The tumor suppressor p53 is highly expressed in neural precursor cells (NPCs) and has an important role in the regulation of both autophagy and apoptosis. We hypothesized that altered lysosome function would lead to NPC death via an interaction between autophagy-and apoptosis-associated proteins. To test our hypothesis, we utilized FGF2-expanded NPCs and the neural stem cell line, C17.2, in combination with the lysosomotropic agent chloroquine (CQ) and the vacuolar ATPase inhibitor bafilomycin A1 (Baf A1). Both CQ and Baf A1 caused concentration-and time-dependent AV accumulation, p53 phosphorylation, increased damage regulator autophagy modulator levels, caspase-3 activation, and cell death. Short hairpin RNA knockdown of Atg7, but not Beclin1, expression significantly inhibited CQ-and Baf A1-induced cell death, indicating that Atg7 is an upstream mediator of lysosome dysfunction-induced cell death. Cell death and/or caspase-3 activation was also attenuated by protein synthesis inhibition, p53 deficiency, or Bax deficiency, indicating involvement of the intrinsic apoptotic death pathway. In contrast to lysosome dysfunction, starvation-induced AV accumulation was inhibited by either Atg7 or Beclin1 knockdown, and Atg7 knockdown had no effect on starvation-induced death. These findings indicate that Atg7-and Beclin1-induced autophagy plays a cytoprotective role during starvation but that Atg7 has a unique pro-apoptotic function in response to lysosome dysfunction.

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Section: Lysosome Dysfunction and Cell Starvation Induce An Increasementioning

confidence: 90%

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Walls

Ghosh

Franklin

et al. 2010

Journal of Biological Chemistry

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“…7 Likewise, although autophagy has been implicated in the apoptotic neuronal loss evident in a number of neurodegenerative diseases, 38 studies indicate that the autophagic response can also promote survival. 39,40 Macroautophagy, which is often referred to as autophagy, participates in a number of different cellular processes.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and Autophagy in Photoreceptors Exposed to Oxidative Stress

Kunchithapautham¹,

Rohrer²

2007

Autophagy

155

124

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Studies on human and animal models of retinal dystrophy have suggested that apoptosis may be the common pathway of photoreceptor cell death. Autophagy, the major cellular degradation process in animal cells, is important in normal development and tissue remodeling, as well as under pathological conditions. Previously we provided evidence that genes, whose products are involved in apoptosis and autophagy, may be coexpressed in photoreceptors undergoing degeneration. Here, we investigated autophagy in oxidative stress-mediated cell death in photoreceptors, analyzing the light-damage mouse model and 661W photoreceptor cells challenged with H 2 O 2 .In the in vivo model, we demonstrated a time-dependent increase in the number of TUNEL-positive cells, concomitant with the formation of autophagosomes. In vitro, oxidative stress increased mRNA levels of apoptotic and autophagic marker genes. H 2 O 2 treatment resulted in the accumulation of TUNEL-positive cells, the majority of which contain autophagosomes. To determine whether autophagy and apoptosis might precede each other or co-occur, we performed inhibitor studies. The autophagy inhibitor 3-methyladenine (3-MA), silencing RNA (siRNA) against two genes whose products are required for autophagy (autophagy-related (ATG) gene 5 and beclin 1), as well as the pan-caspase-3 inhibitor, zVAD-fmk, were both found to partially block cell death. Blocking autophagy also significantly decreased caspase-3 activity, whereas blocking apoptosis increased the formation of autophagosomes. The survival effects of 3-MA and zVAD-fmk were not additive; rather treatment with both inhibitors lead to increased cell death by necrosis. In summary, the study first suggests that autophagy participates in photoreceptor cell death possibly by initiating apoptosis. Second, it confirms that cells that normally die by apoptosis will execute cell death by necrosis if the normal pathway is blocked. And third, these results argue that the up-stream regulators of autophagy need to be identified as potential therapeutic targets in photoreceptor degeneration.

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“…Since apoptosis is associated with an increase in mitochondrial permeability, it is not entirely surprising that mitophagy is observed in cells that subsequently die by apoptosis in several mammalian cell systems. 7,8,43 Sympathetic neurons die within a few days after nerve growth factor (NGF) withdrawal and the cell death is characterized by an early increase in autophagosomes containing the mitochondria and other cytoplasmic components, followed by degradation of organelles within the autophagosome. 7 The classical features of apoptosis appear at later time points.…”

Section: Factors That Increase Mitochondrial Permeability Promote Degmentioning

confidence: 99%

Macroautophagy versus mitochondrial autophagy: a question of fate?

Kundu

Thompson²

2005

Cell Death Differ

106

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Autophagy is a catabolic process that allows recycling of cytoplasmic components (including organelles) into basic components, offering a bioenergetically efficient alternative to de novo synthesis. In yeast, autophagy functions primarily as an adaptive mechanism allowing survival in the response to changes in the availability of nutrients in the environment. Over the past decade, genetic screens performed in yeast have elucidated many of the molecular components involved in this adaptive response. [1][2][3] More recently, the roles of homologous genes are being explored in multicellular organisms and in cells derived from these organisms. 4 These studies have demonstrated that while autophagy is often induced as part of an adaptive response, induction of autophagy may also lead to cell death. During Drosophila larval development, for example, starvation-induced autophagy occurs in the larval fat body and is required for maintaining circulating nutrient levels and survival of the larvae under unfavorable nutritional conditions; 5 by contrast, programmed autophagy results in cell death and is the primary means of removing certain larval organs during metamorphosis. 6 On a cellular level, autophagy is observed prior to apoptosis in growth factor-deprived neuronal cultures. 7,8 In cells lacking critical proapoptotic proteins, the adaptive process of autophagy aimed at maintaining bioenergetic homeostasis can be unmasked in response to growthfactor withdrawal. 9 In contrast, cell death in response to a variety of chemicals has been suggested to result from autophagic destruction of the cell and to be suppressed by inhibition of autophagy. 10 The factors that determine whether induction of autophagy contributes to cell survival or cell death are not well-elucidated; however, two key issues may be the rate of autophagic degradation and the specificity of the engulfed components. Although autophagy is generally considered a nonspecific process, there are instances where the mitochondria (and other organelles) appear to be specifically targeted. Here, we focus on the signals and pathways involved in regulating the induction of autophagy and mitochondrial autophagy in yeast and how these processes are relevant to survival and death of mammalian cells.In general terms, 'autophagy' refers to any intracellular process that involves the degradation of cytosolic components by the lysosome. There are at least three distinct autophagic pathways: macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy is a multistep process by which portions of cytoplasm and/or organelles are sequestered in a double or multimembrane structure ('autophagosome') and delivered to the lysosome for degradation (Figure 1). Upon fusion of the autophagosome with the lysosome, it becomes an autophagolysosome or autophagic vacuole. Although macroautophagy is generally considered a nonspecific process there are instances in which organelles, such as mitochondria and peroxisomes, appear to be preferentially sequestered. These process...

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Role of the autophagic‐lysosomal system on low potassium‐induced apoptosis in cultured cerebellar granule cells

Cited by 122 publications

References 73 publications

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Lysosome Dysfunction Triggers Atg7-dependent Neural Apoptosis

Apoptosis and Autophagy in Photoreceptors Exposed to Oxidative Stress

Macroautophagy versus mitochondrial autophagy: a question of fate?

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