Autophagy in human health and disease pdf
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- Autophagy in Health and Disease, Volume 172
- Transautophagy: Research and Translation of Autophagy Knowledge 2020
- Emerging role of selective autophagy in human diseases
- Autophagy: Everything you need to know
Crosstalk between autophagy and apoptosis: Mechanisms and therapeutic implications Andrew Thorburn 5.
Autophagy in Health and Disease, Volume 172
Molecular mechanisms protecting against tissue injury View all 9 Articles. Autophagy was originally described as a highly conserved system for the degradation of cytosol through a lysosome-dependent pathway.
In response to starvation, autophagy degrades organelles and proteins to provide metabolites and energy for its pro-survival effects. Autophagy is recognized as playing a role in the pathogenesis of disease either directly or indirectly, through the regulation of vital processes such as programmed cell death, inflammation, and adaptive immune mechanisms. Recent studies have demonstrated that autophagy is not only a simple metabolite recycling system, but also has the ability to degrade specific cellular targets, such as mitochondria, cilia, and invading bacteria.
In addition, selective autophagy has also been implicated in vesicle trafficking pathways, with potential roles in secretion and other intracellular transport processes. Selective autophagy has drawn the attention of researchers because of its potential importance in clinical diseases.
Therapeutic strategies to target selective autophagy rather than general autophagy may maximize clinical benefit by enhancing selectivity. In this review, we outline the principle components of selective autophagy processes and their emerging importance in human disease, with an emphasis on pulmonary diseases.
Autophagy is a lysosomal degradation system by which the cell can recycle its cytoplasmic components Mizushima and Komatsu, At present, three different types of autophagic pathways have been reported, named as macroautophagy, microautophagy, and chaperone-mediated autophagy Mizushima and Komatsu, Autophagy proceeds through sequential steps, beginning with the generation of autophagosomes from an isolation membrane and followed by elongation to form a mature autophagosome which captures cytosolic cargo Mizushima and Komatsu, Genetic studies in yeast have identified a series of autophagy-related genes ATGs shown to be essential for the autophagy process Tsukada and Ohsumi, ; Klionsky et al.
Among these, microtubule associated protein 1 light chain-3 LC3 , a homologue of yeast Atg8, is converted from a cytosolic form LC3-I to its phosphatidylethanolamine-conjugated form LC3-II which targets to autophagic membranes Mizushima et al.
Autophagosome formation is also regulated by the autophagy protein Beclin 1 homolog of yeast Atg6; Liang et al. The membrane origin of autophagosomes remains unclear. Although the endoplasmic reticulum ER , mitochondria and plasma membrane have been reported as the membrane source, recent studies have also suggested that the ER-mitochondria contact site is important in autophagosome formation Hailey et al.
Subsequently, the autophagosome containing the cytosolic components and organelles fuses with the lysosome to form the autolysosome where the sequestered cargo is degraded Mizushima and Komatsu, Initial studies on the molecular mechanisms of autophagy have largely focused on the early stage, however, precise mechanisms of the late stage where the autophagosome fuses with the lysosome have also been revealed Shen and Mizushima, Recent studies have demonstrated that the transcription factor EB TFEB , a master gene for lysosomal biogenesis, coordinates the autophagic process by driving expression of autophagy and lysosomal related genes Settembre et al.
An autophagosomal soluble N -ethylmaleimide-sensitive factor attachment protein receptor SNARE has been identified as the regulator of autophagosome—lysosome fusion Itakura et al.
Each selective autophagy subtype was named after its specific targets, for example: aggregated proteins aggrephagy; Yamamoto and Simonsen, , mitochondria mitophagy; Youle and Narendra, , pathogens xenophagy; Levine et al. Selective autophagy is also related to vesicle trafficking pathways, and its importance in secretion and other intracellular transport processes is rapidly increasing Stolz et al.
Previous studies suggest that autophagy is relevant to human diseases, including pulmonary diseases Levine and Kroemer, ; Choi et al. Furthermore, convincing evidence that selective autophagy may be implicated in human disease has been reported Gomes and Dikic, ; Redmann et al.
This led us to the hypothesis that selective autophagy would impact the pathogenesis of pulmonary diseases. In this review, we will examine the considerable evidence emerging for the role of selective autophagy in the pathogenesis of complex pulmonary diseases.
A better understanding of the role s of selective autophagy in disease pathogenesis may help design more specific therapies for the treatment of pulmonary diseases, and other diseases where autophagy may contribute to pathogenesis. Selective autophagy can deliver a wide range of cargo to the lysosome, including protein aggregates, whole organelles e.
Although the mechanisms of selective degradation remain incompletely understood, several reports suggest that ubiquitination of substrates may serve as general tag for selective autophagy in mammalian cells Kirkin et al. Recent studies have described important functions of Atg8 family proteins in selective autophagy, including interactions with cargo receptors and components of the basal autophagy machinery, and in the regulation of autophagosome biogenesis Kaufmann et al.
To evaluate the inclusive list of selective autophagy processes currently in the literature is beyond the scope of this review; we will therefore focus on the three types of selective autophagy most related to pulmonary diseases; mitophagy, xenophagy, and ciliophagy.
Mitophagy is a selective mechanism for the elimination of mitochondria through the autophagic machinery Youle and Narendra, A proposal for the mechanism of mitophagy is that damaged and depolarized mitochondria stabilize PINK1 which in turn recruits the E3 ubiquitin ligase, Parkin. However, several previous reports are suggestive of PINK1-dependent, but Parkin-independent, mitophagy. Gp78 E3 ubiquitin ligase overexpression causes mitophagy that is independent of Parkin Fu et al.
Mice genetically deficient in Pink1 were resistant to Staphylococcus aureus -induced acute lung injury ALI. PINK1 was found to interact with an alternative ubiquitin E3 ligase component, F-box only protein 15 Fbxo15 , which promoted mitochondrial instability in this model Chen et al. Furthermore, although mitophagy was generally considered to serve as an intrinsic mitochondrial quality control system, it has been reported that mitophagy may trigger cell death Sentelle et al.
Now, mitophagy is generally recognized as a potential modulator of the pathogenesis of disease with either protective or harmful consequences. Autophagy receptors including p62, nuclear domain 10 protein 52 NDP52 and optineurin recognize ubiquitinated pathogens and target them to autophagosomes Gomes and Dikic, Besides its direct role in pathogen clearance, xenophagy may also serve host defenses by enhancing immune recognition of infected cells via the generation of antigenic bacterial peptides Yano and Kurata, Meanwhile, some bacteria, such as S.
These bacteria can not only block autophagosomal maturation and acidification, but also can proliferate in LC3-positive compartments Gomes and Dikic, Recently, we have demonstrated that an autophagy-dependent pathway regulates cilia length Lam et al.
Pampliega et al. On the other hand, it has reported that autophagy removes oral-facial-digital syndrome 1 protein OFD1 from centriolar satellites to promote ciliogenesis Tang et al. However, the precise mechanisms by which autophagy can regulate these conflicting processes remains to be elucidated Wrighton, Chronic obstructive pulmonary disease COPD contributes significantly to the global burden of disease as the fourth leading cause of mortality worldwide, however, the pathogenesis of this disease remains incompletely understood Dal-Re, ; Vestbo et al.
In an in vivo emphysema model, genetic deletion of specific autophagy proteins reduced airspace enlargement Chen et al.
More recently, we demonstrated that mitophagy regulates necroptosis, a form of programmed necrosis, which contributes to the pathogenesis of COPD Mizumura et al. Cigarette smoke CS exposure induced mitophagy through the stabilization of the mitophagy regulator PINK1 in pulmonary epithelial cells. Mice genetically deficient in PINK1 were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance MCC disruption during CS exposure.
In this study, we have shown that significant mitochondrial depolarization occurred in pulmonary epithelial cells in response to CS extract CSE exposure.
Moreover, our results suggest that active mitophagy may alter mitochondrial membrane integrity, and lead to the induction of necroptosis.
However, the precise mechanism by which mitophagy can serve to aggravate mitochondrial injury in the CS exposure model remains obscure. One possible hypothesis is that CS-induced aberrant mitophagy may cause an increase in the population of impaired mitochondria Figure 1A. Further studies are necessary to improve the understanding of the role of mitophagy in the pathogenesis of COPD.
Selective autophagy in chronic obstructive pulmonary disease COPD. Cigarette smoke CS induced mitochondrial fission and PINK1-dependent mitophagy in epithelial cells independently from mitochondrial damage. This aberrant mitophagy may cause the increase in the population of impaired mitochondria, which leads to the initiation of necroptosis. CS induces oxidative stress, which causes cilia protein damage. Damaged cilia proteins are ubiquitinated which promotes aggregate formation.
HDAC6 recognizes ubiquitinated protein aggregates and delivers them to autophagosomes. We also reported that ciliophagy, the consumption of cilia components by autophagy, regulates cilia length during CS exposure Figure 1B ; Lam et al. Impaired airway clearance caused by cilia shortening prevents the elimination of pathogens from the airways and may cause recurrent respiratory infections that exacerbate COPD. We identified the cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure Lam et al.
In contrast, previous studies have demonstrated defective autophagy in CS-exposed macrophages Monick et al. The mechanism of antibacterial autophagy in Mycobacterium tuberculosis Mtb infection is well-characterized. The lungs are the major site for Mtb infection. Mtb employs a unique strategy for survival that interferes with the fusion between phagosomal compartments containing Mtb and lysosomes Vergne et al.
Despite the availability of anti-TB drugs, recent reports have identified cases of totally drug-resistant TB Loewenberg, ; Udwadia et al. Since new therapeutic agents that have different mechanisms of action from conventional anti-TB drugs are needed to prevent the development of drug resistance, bacterial autophagy xenophagy has drawn attention as a candidate therapeutic target.
Recent studies have revealed that Mtb extracellular DNA activates ubiquitin-mediated selective autophagy through phagosomal permeabilization Figure 2B ; Watson et al. The bacterial early secretory antigenic target 6 ESAT-6 system 1 ESX-1 secretion system mediates phagosomal permeabilization to enable the ubiquitin-mediated autophagy pathway access to phagosomal Mtb.
Autophagy receptors, p62, and NDP52, recognize ubiquitinated Mtb and target them to autophagosomes. Several therapies that involve enhancing autophagy activity also have been proposed to be effective against Mtb infection. The antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy through inhibition of mTORC1 signaling, which in turn prevents intracellular proliferation of Mtb Lam et al.
Vitamin D has revealed therapeutic benefits in persons with HIV and Mtb infection through the activation of autophagy Campbell and Spector, Selective autophagy in respiratory infection and sepsis. A The role of autophagy in Mycobacterium tuberculosis Mtb infection. B The role of selective autophagy in Mtb infection.
The bacterial ESX-1 secretion system mediates phagosomal permeabilization to enable the ubiquitin-mediated autophagy pathway to access phagosomal Mtb. Ubiquitinated Mtb is recognized by p62 and NDP52 as a target of selective autophagy. C The role of mitophagy in sepsis. Autophagy has been implicated in the regulation of inflammation, particularly the regulation of the inflammasome pathway.
Inflammasomes represent an inflammatory signaling platform activated by infection or stress that regulate the maturation and secretion of pro-inflammatory cytokines e. Along with Zhou et al, we have demonstrated that suppression of autophagy causes the accumulation of damaged ROS-producing mitochondria, whereas activates the NLRP3 inflammasome Figure 2C ; Nakahira et al.
Recently, we have also demonstrated that carbon monoxide CO confers protection in sepsis by enhancing Beclin 1-dependent autophagy and phagocytosis Lee et al. These results suggest that CO gas may represent a novel therapy for patients with sepsis. We have demonstrated that autophagy is implicated in the pathogenesis of ALI Tanaka et al.
Although mechanical ventilation with high concentrations of oxygen is required to manage patients with severe respiratory failure, prolonged exposure to hyperoxia can result in lung injury.
Hyperoxia can induce autophagy activity. We also investigated the molecular mechanism by which autophagy can confer cytoprotection in lung epithelial cells after hyperoxia Liang et al. Increased tBID causes cytochrome c release from the mitochondria and subsequent caspase-dependent cell death. These results suggest that the autophagy may have protective function during the pathogenesis of ALI, especially under hyperoxia. It has been reported that mechanical ventilation and hyperoxia cause pulmonary mitochondrial dysfunction Ratner et al.
Given that mitochondrial damage can induce mitophagy, it is reasonable to presume that mitophagy may play a role in the pathogenesis of ALI Youle and Narendra, Indeed, the role of mitophagy in hyperoxia has been reported.
Transautophagy: Research and Translation of Autophagy Knowledge 2020
Autophagy is an essential mechanism to sustain homeostasis at cellular and organismal levels. Concerning human health, an increasing number of examples underline its value as a novel therapeutic target since autophagy modulation may potentially become an effective new strategy to combat cancer, neurodegeneration, and infection. Beneficially, autophagy modulation may also slow down age-related tissue decline. A relationship between redox disorder and autophagy signaling has already been described but is still not well characterized. Oxidative stress can arise in cells because of different reasons; among them are metal imbalance and perturbation or perforation of cellular membranes by various insults. In addition, it has been recently hypothesized that amyloid prefibrillar oligomers and proteostasis constitute a metabolic balance between synthesis and degradation of proteins, with protein misfolding and accumulation of the aggregated proteins shifting the balance. All these processes are in a direct or indirect way relying on good performance of autophagy to clear the cells of unnecessary burdens and thus rejuvenate them.
It seems that you're in Germany. We have a dedicated site for Germany. The chapters cover autophagy and its potential applications on diseases ranging from obesity, osteoarthritis, pulmonary fibrosis, and inflammation, through ALS, Parkinson's, retinal degeneration, breast cancer, alcoholic liver disease and more. The final chapters round out the book with a discussion of autophagy in drug discovery and 'bench to bedside'. Chapters are contributed by leading authorities and describe the general concepts of autophagy in health and disease, marrying cell biology and pharmacology and covering: studies derived from preclinical experiments, manufacturing considerations,and regulatory requirements pertaining to drug discovery and manufacturing and production.
Emerging role of selective autophagy in human diseases
Researchers have linked autophagy to several positive health effects. They also believe that a person might be able to induce autophagy by fasting. However, it is important to remember that much of the research into autophagy is in its early stages.
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Autophagy: Everything you need to know
If the address matches an existing account you will receive an email with instructions to reset your password. If the address matches an existing account you will receive an email with instructions to retrieve your username. Address correspondence to: Prof. Significance: In eukaryotes, autophagy represents a highly evolutionary conserved process, through which macromolecules and cytoplasmic material are degraded into lysosomes and recycled for biosynthetic or energetic purposes. Dysfunction of the autophagic process has been associated with the onset and development of many human chronic pathologies, such as cardiovascular, metabolic, and neurodegenerative diseases as well as cancer.
Autophagy is the natural cellular process of construction and destruction mechanisms involved in physiological development and pathological genesis. From embryogenesis to post-natal development, autophagy or autophagocytosis plays a critical role in tissue and organ architecture along with the differentiation of normal tissue and remodelling of pathological advancement. Aiming to expand the therapeutic potential of autophagy, many researchers focus on developing new drugs or treatment strategies for Parkinson's disease, rheumatic diseases and oncogenesis by controlling cell fate via regulating molecular pathways. This series aims to highlight essential molecular and cellular mechanisms for understanding autophagy and its comprehensive associations with cardiac vascular diseases, carcinogenesis, liver diseases, neuronal degeneration and other related disorders. Original research papers and review articles will be considered for publication in this series. Autophagy is a prominent mechanism to preserve homeostasis and the response to intracellular or extracellular stress.
Four forms of autophagy have been identified: macroautophagy , microautophagy , chaperone-mediated autophagy CMA , and crinophagy. In crinophagy the least well-known and researched form of autophagy , unecessary secretory granules are degraded and recycled. In disease, autophagy has been seen as an adaptive response to stress, promoting survival of the cell; but in other cases it appears to promote cell death and morbidity. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels. The word "autophagy" was in existence and frequently used from the middle of the 19th century. Autophagy was first observed by Keith R.
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