Autophagy Is Activated by Apoptotic Signalling in Sympathetic Neurons: An Alternative Mechanism of Death Execution

Xue, Luzheng; Fletcher, Graham C.; Tolkovsky, Aviva M.

doi:10.1006/mcne.1999.0780

Cited by 417 publications

(370 citation statements)

References 55 publications

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“…During apoptosis, mitochondria are acknowledged as a central element; recently, some reports have suggested the involvement of mitochondria in autophagy also. [16][17][18][19] Here, we report for the first time, the occurrence of autophagy as a consequence of a physiological mitochondrial dysfunction in yeast, resulting from either anaerobic and heat stress growth of a FMC1 null mutant or anaerobic growth of a strain carrying a point mutation in the ATP2 gene. This mitochondrial dysfunction results in the collapse of the electrical potential across the mitochondrial inner membrane (DC), while not decreasing the cellular ATP concentration.…”

Section: Introductionmentioning

confidence: 86%

Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast

et al. 2005

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Autophagy, a highly regulated programme found in almost all eukaryotes, is mainly viewed as a catabolic process that degrades nonessential cellular components into molecular building blocks, subsequently available for biosynthesis at a lesser expense than de novo synthesis. Autophagy is largely known to be regulated by nutritional conditions. Here we show that, in yeast cells grown under nonstarving conditions, autophagy can be induced by mitochondrial dysfunction. Electron micrographs and biochemical studies show that an autophagic activity can result from impairing the mitochondrial electrochemical transmembrane potential. Furthermore, mitochondrial damage-induced autophagy results in the preferential degradation of impaired mitochondria (mitophagy), before leading to cell death. Mitophagy appears to rely on classical macroautophagy machinery while being independent of cellular ATP collapse. These results suggest that in this case, autophagy can be envisioned either as a process of mitochondrial quality control, or as an ultimate cellular response triggered when cells are overwhelmed with damaged mitochondria.

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Section: Introductionmentioning

confidence: 86%

Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast

et al. 2005

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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%

“…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. Inhibition of autophagy using 3-methyladenine (3-MA, an inhibitor of Class III PI3 kinase) also blocks apoptosis with overlapping dose-response curves, suggesting that there may be a common signaling pathway that activates both autophagy and apoptosis.…”

Section: Factors That Increase Mitochondrial Permeability Promote Degmentioning

confidence: 99%

“…Inhibition of autophagy using 3-methyladenine (3-MA, an inhibitor of Class III PI3 kinase) also blocks apoptosis with overlapping dose-response curves, suggesting that there may be a common signaling pathway that activates both autophagy and apoptosis. 7 Furthermore, treatment of NGF-deprived neurons with the pan-caspase inhibitor, Boc-Asp-(OMe)-fluoromethylketone (BAF), prevents apoptosis, but the mitochondria selectively disappear by autophagy within three days and the cells die shortly thereafter. 8 Similarly, in Hela cells treated with BAF for the duration of the culture, a 9-h incubation with staurosporin results in complete mitochondrial loss via autophagy within 3 days after removal of staurosporine.…”

Section: Factors That Increase Mitochondrial Permeability Promote Degmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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