Autophagy fights disease through cellular self-digestion

doi:10.1038/NATURE06639

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Autophagy fights disease through cellular self-digestion

Journal Article•DOI•

Autophagy fights disease through cellular self-digestion

Noboru Mizushima¹, Beth Levine², Ana Maria Cuervo³, Daniel J. Klionsky⁴•Institutions (4)

Tokyo Medical and Dental University¹, University of Texas at Dallas², Yeshiva University³, University of Michigan⁴

28 Feb 2008-Nature (Nature Publishing Group)-Vol. 451, Iss: 7182, pp 1069-1075

TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.

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Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

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Journal Article•DOI•

The Hallmarks of Aging

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Carlos López-Otín¹, Maria A. Blasco, Linda Partridge², Manuel Serrano, Guido Kroemer² - Show less +1 more•Institutions (2)

University of Oviedo¹, Max Planck Society²

06 Jun 2013-Cell

TL;DR: Nine tentative hallmarks that represent common denominators of aging in different organisms are enumerated, with special emphasis on mammalian aging, to identify pharmaceutical targets to improve human health during aging, with minimal side effects.

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9,980 citations

Cites background from "Autophagy fights disease through ce..."

...Proteostasis involves mechanisms for the stabilization of correctly folded proteins—most prominently, the heatshock family of proteins—and mechanisms for the degradation of proteins by the proteasome or the lysosome (Hartl et al., 2011; Koga et al., 2011; Mizushima et al., 2008)....
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...Proteostasis involves mechanisms for the stabilization of correctly folded proteins, most prominently the heat-shock family of proteins, and mechanisms for the degradation of proteins by the proteasome or the lysosome (Hartl et al., 2011; Koga et al., 2011; Mizushima et al., 2008)....
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Journal Article•DOI•

Methods in Mammalian Autophagy Research

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Noboru Mizushima¹, Tamotsu Yoshimori², Beth Levine³•Institutions (3)

Tokyo Medical and Dental University¹, Osaka University², University of Texas Southwestern Medical Center³

05 Feb 2010-Cell

TL;DR: Methods to monitor autophagy and to modulate autophagic activity are discussed, with a primary focus on mammalian macroautophagy.

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3,998 citations

Cites background from "Autophagy fights disease through ce..."

...Under physiological conditions, autophagy has a number of vital roles such as maintenance of the amino acid pool during starvation, preimplantation development, prevention of neurodegeneration, antiaging, tumor suppression, clearance of intracellular microbes, and regulation of innate and adaptive immunity (Cecconi and Levine, 2008; Deretic and Levine, 2009; Levine and Kroemer, 2008; Mizushima et al., 2008; Rubinsztein, 2006)....
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...in part, from increased autophagy (based on microscopic visualization of increased numbers of early intermediates in the pathway) when, in reality, the accumulation of early intermediates in such diseases likely represents a block in later stages of the autophagy pathway (Levine and Kroemer, 2008; Mizushima et al., 2008; Rubinsztein, 2006)....
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...…microscopic visualization of increased numbers of early intermediates in the pathway) when, in reality, the accumulation of early intermediates in such diseases likely represents a block in later stages of the autophagy pathway (Levine and Kroemer, 2008; Mizushima et al., 2008; Rubinsztein, 2006)....
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...…preimplantation development, prevention of neurodegeneration, antiaging, tumor suppression, clearance of intracellular microbes, and regulation of innate and adaptive immunity (Cecconi and Levine, 2008; Deretic and Levine, 2009; Levine and Kroemer, 2008; Mizushima et al., 2008; Rubinsztein, 2006)....
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...Moreover, increasing evidence suggests that the deregulation of autophagy may contribute to a broad spectrum of mammalian diseases (Levine and Kroemer, 2008; Mizushima et al., 2008)....
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Journal Article•DOI•

Autophagy regulates lipid metabolism

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Rajat Singh¹, Susmita Kaushik, Yongjun Wang, Youqing Xiang, Inna Novak¹, Masaaki Komatsu², Keiji Tanaka², Ana Maria Cuervo, Mark J. Czaja - Show less +5 more•Institutions (2)

Albert Einstein College of Medicine¹, Institute of Medical Science²

30 Apr 2009-Nature

TL;DR: A previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy) is identified that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.

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Abstract: The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.

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3,091 citations

Journal Article•DOI•

Autophagy and the Integrated Stress Response

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Guido Kroemer¹, Guillermo Mariño¹, Guillermo Mariño², Beth Levine³•Institutions (3)

French Institute of Health and Medical Research¹, Institut Gustave Roussy², University of Texas Southwestern Medical Center³

22 Oct 2010-Molecular Cell

TL;DR: Autophagy is a cell biological process that is a central component of the integrated stress response and can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli.

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3,002 citations

Journal Article•DOI•

Repertoires of Autophagy in the Pathogenesis of Ocular Diseases

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Yu-Jie Li¹, Qin Jiang, Guo-Fan Cao, Jin Yao, Biao Yan - Show less +1 more•Institutions (1)

Nanjing Medical University¹

01 Apr 2015-Cellular Physiology and Biochemistry

TL;DR: In this manuscript, the relevant progress about the role of autophagy in the pathogenesis of ocular diseases is reviewed and pharmacological manipulation of Autophagy may provide an alternative therapeutic target for some Ocular diseases.

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Abstract: Autophagy is an important intracellular degradative process that delivers cytoplasmic proteins to lysosome for degradation. Dysfunction of autophagy is implicated in several human diseases, such as neurodegenerative diseases, infectious diseases, and cancers. Autophagy-related proteins are constitutively expressed in the eye. Increasing studies have revealed that abnormal autophagy is an important pathological feature of several ocular diseases. Pharmacological manipulation of autophagy may provide an alternative therapeutic target for some ocular diseases. In this manuscript, we reviewed the relevant progress about the role of autophagy in the pathogenesis of ocular diseases.

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2,571 citations

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Journal Article•DOI•

Autophagy in the Pathogenesis of Disease

[...]

Beth Levine¹, Guido Kroemer², Guido Kroemer³, Guido Kroemer⁴•Institutions (4)

University of Texas Southwestern Medical Center¹, Institut Gustave Roussy², French Institute of Health and Medical Research³, University of Paris-Sud⁴

11 Jan 2008-Cell

TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

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6,301 citations

Journal Article•DOI•

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

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Taichi Hara¹, Kenji Nakamura², Makoto Matsui³, Makoto Matsui¹, Makoto Matsui⁴, Akitsugu Yamamoto⁵, Yohko Nakahara², Rika Suzuki-Migishima², Minesuke Yokoyama⁶, Kenji Mishima⁷, Ichiro Saito⁷, Hideyuki Okano⁸, Noboru Mizushima¹ - Show less +9 more•Institutions (8)

Institute of Medical Science¹, Mitsubishi², Graduate University for Advanced Studies³, National Institute for Basic Biology, Japan⁴, Nagahama Institute of Bio-Science and Technology⁵, Niigata University⁶, Tsurumi University⁷, Keio University⁸

15 Jun 2006-Nature

TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

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Abstract: Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

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3,684 citations

Journal Article•DOI•

p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy

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Serhiy Pankiv¹, Terje Høyvarde Clausen¹, Trond Lamark¹, Andreas Brech², Jack-Ansgar Bruun¹, Heidi Outzen¹, Aud Øvervatn¹, Geir Bjørkøy¹, Terje Johansen¹ - Show less +5 more•Institutions (2)

University of Tromsø¹, Oslo University Hospital²

17 Aug 2007-Journal of Biological Chemistry

TL;DR: It is demonstrated that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation and p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.

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3,676 citations

Journal Article•DOI•

Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.

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Sophie Pattingre¹, Sophie Pattingre², Amina T. Tassa², Xueping Qu¹, Xueping Qu², Rita Garuti², Xiao Huan Liang¹, Noboru Mizushima³, Milton Packer², Michael D. Schneider⁴, Beth Levine², Beth Levine¹ - Show less +8 more•Institutions (4)

Columbia University¹, University of Texas Southwestern Medical Center², Institute of Medical Science³, Baylor College of Medicine⁴

23 Sep 2005-Cell

TL;DR: Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1, which may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.

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3,384 citations

Journal Article•DOI•

Loss of autophagy in the central nervous system causes neurodegeneration in mice

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Masaaki Komatsu¹, Satoshi Waguri², Satoshi Waguri³, Tomoki Chiba¹, Shigeo Murata¹, Junichi Iwata⁴, Junichi Iwata¹, Isei Tanida⁴, Takashi Ueno⁴, Masato Koike², Yasuo Uchiyama², Eiki Kominami⁴, Keiji Tanaka¹ - Show less +9 more•Institutions (4)

Institute of Medical Science¹, Osaka University², Fukushima Medical University³, Juntendo University⁴

15 Jun 2006-Nature

TL;DR: It is found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.

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Abstract: Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy--the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover--in the protein quality-control process. However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.

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3,349 citations