Autophagy: molecular machinery for self-eating

Yorimitsu, Tomohiro; Klionsky, Daniel J.

doi:10.1038/sj.cdd.4401765

Cited by 1,397 publications

(1,237 citation statements)

References 91 publications

(126 reference statements)

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“…Autophagy is controlled by a group of evolutionarily conserved genes (ATG genes) (28,29) that control a coordinated process leading to the induction and nucleation of autophagic vesicles, their completion, expansion and fusion with lysosomes and breakdown and recycling. Over 30 ATG genes have been identified in yeast and at least 11 (ATG 1,3,4,5,6,7,8,9,10,12 and 16) have orthologs in mammals, Atg6 is also known as Beclin1 and Atg8 is commonly called LC3 in mammals.…”

Section: Regulation Of Autophagymentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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Section: Regulation Of Autophagymentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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“…The implication of this is that impaired autophagy might result in defective proteasomes since they, together with mitochondria and other organelles, are then not properly renewed. The mechanisms involved in the formation of the autophagic double membrane (the phagophore), the inclusion of materials to be degraded, and the fusion of autophagosomes and lysosomes were recently elucidated as a result of the discovery in yeast of a large family of phylogenetically well preserved autophagy-related genes (ATG) (Klionsky, 2007, Shintani and Klionsky, 2004, Suzuki and Ohsumi, 2007, Yorimitsu and Klionsky, 2005). …”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

“…within which the degradation of the cargo and the recycling of amino acids and other monomeric molecules, occurs (Cuervo, 2004, Kurz et al, 2008b, Yorimitsu and Klionsky, 2005.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

“…Autophagy has recently been found to be a highly controlled process that is regulated by a large number of conserved autophagy related genes (ATGs) and is of fundamental importance for cellular survival (Klionsky, 2007, Shintani and Klionsky, 2004, Suzuki and Ohsumi, 2007, Yorimitsu and Klionsky, 2005. The autophagic degradation of iron-containing materials, such as ferritin and mitochondrial complexes, explains the presence of lysosomal redox-active iron.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

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The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

175

134

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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“…1 Whereas growth factors enhance the ability of metazoan cells to take up extracelluar nutrients and suppress autophagy, deprivation of either growth factors or extracellular nutrients leads to decreased nutrient uptake and derepression of autophagy. The catabolic autophagy process is believed to allow starving cells to support adenosine triphosphate (ATP) production and avoid cell death.…”

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DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

et al. 2006

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Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagyassociated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased nonapoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance. Autophagy is a process by which subcellular constituents are degraded in autophagosomes/autolysosomes in response to stress. 1 Whereas growth factors enhance the ability of metazoan cells to take up extracelluar nutrients and suppress autophagy, deprivation of either growth factors or extracellular nutrients leads to decreased nutrient uptake and derepression of autophagy. The catabolic autophagy process is believed to allow starving cells to support adenosine triphosphate (ATP) production and avoid cell death. 2,3 The autophagic process is regulated by both class I and class III phosphatidylinositol 3-kinase (PI3K) pathways. 2,4,5 Mammalian target of Rapamycin (mTOR) functions downstream of the class-I PI3K/Akt, and is a key negative regulator of autophagy. In this role, mTOR serves as a metabolic sensor that coordinates crosstalk between nutrient availability and autophagy. 6,7 In contrast, class III PI3K positively regulates autophagy. The formation of a preautophagosomal isolation membrane that encloses cytoplasmic cargo is positively regulated by phosphatidylinositol 3-phosphate, the products of class III PI3K phosphorylation. 4 It has also been suggested that the trafficking of autophagosomes is regulated by class III PI3Ks, 4,5 an idea supported by the observation that 3-methyladenine (3-MA), which inhibits class III PI3K activity, also inhibits autophagosome formation and is widely used as an autophagy inhibitor. 5 It is also known that autophagy is induced in cancer cells derived from tissues such as breast, colon, prostate and brain in response to a variety of anticancer therapies. 3,8 However, autophagy in response to these drugs can produce different outcomes, in some cases promoting cell adaptation and survival similar to what is seen in nutrient deprived cells, while in other cases, inducing programmed cell death type. The role of drug-induced autophagy in cell death or surv...

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Autophagy: molecular machinery for self-eating

Cited by 1,397 publications

References 91 publications

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Apoptosis and autophagy: regulatory connections between two supposedly different processes

The role of lysosomes in iron metabolism and recycling

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

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