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Autophagy Mechanism - Mitophagy

Autophagy and autophagy-related diseases -

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Department of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, , USA. Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, , USA.

You can also search for this author in PubMed Google Scholar. BM and SH carried out the design of this review. BM drafted the manuscript and prepared the Figs. BM and XL made substantial contributions to the conception. BM, XL, and SH collected the related references and revised the manuscript.

BM and SH revised and improved the language. The authors read and approved the final manuscript. Correspondence to Binyun Ma. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Li, X. Autophagy and autophagy-related proteins in cancer. Mol Cancer 19 , 12 Download citation.

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Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related ATG proteins in cancer.

Introduction Fifty years ago, Christian de Duve, a Belgian scientist, firstly coined the term autophagy at the Ciba Foundation symposium on lysosomes in [ 1 , 2 ], for which he shared the Nobel Prize in Physiology or Medicine in with Albert Claude and George E. Full size image.

Molecular basis of autophagy Only a small amount of autophagy in cells is involved in maintaining homeostasis in physiological condition. Process of autophagy Physiologically, autophagy is an evolutionarily conserved, self-degradative, normal physiological process in cells, which is composed of several closely related steps including induction of autophagy, assembly and formation of autophagosome, autophagosome docking and fusion with lysosomal membranes, and degradation and recirculation of intra-autophagosomal contents in autophagolyosome [ 17 , 31 ] Fig.

Induction of autophagy Induction of autophagy can be triggered by several intracellular and extracellular stimulus, e. Assembly and formation of autophagosome Final formation of mature autophagosome includes nucleation of the multiple Atg proteins at PAS, elongation of the isolation membrane, and maturation of autophagosome, and four functional units are involved in these processes Fig.

Autophagosome fusion with lysosomal membranes Autophagosome docking and fusion with lysosomal membranes require the mature autophagosomes which will be transported to the perinuclear region for the autophagosome-lysosome fusion [ 44 ]. Degradation and recirculation of autophagosomal contents When autophagosome fuses with lysosomes to form autophagolyosome, many enzymes in lysosomes, e.

Autophagy-related proteins Although autophagic structures by electron microscopy examination were firstly reported by Christian de Duve under 60 years ago, the molecular mechanism of autophagy regulation remained mostly unknown until discovery of yeast Atg genes in the s, which greatly promoted the mechanistic understanding of autophagy and clarified the fact that autophagy plays important roles in various biological processes [ 46 , 47 , 48 , 49 ].

Table 1 Autophagy-related Atg genes and their protein function in autophagy Full size table. Table 2 ATG proteins of mammals in the core machinery of autophagosome formation Full size table. Autophagy in cancer Physiologically, autophagy, by eliminating damaged proteins and organelles during stress and aging, plays critical roles in regulating organismal development, cooperating with the adaptive immune system, sustaining energy homeostasis and maintaining protein and organelle quality control [ 11 , , , , , ].

Dual role of autophagy in cancer In cancer development, autophagy plays a dual role depending on type, stage or genetic context of the cancers [ , , , , , ]. Conclusions and perspectives Autophagy, as a cell survival pathway, plays an important role in cancer, and can help to prevent bioenergetic failure by metabolic stress and maintain protein and organelle quality and quantity, and contributes to all aspects of tumorigenesis, including tumor initiation, progression and development, and maintenance of the malignant state.

Availability of data and materials Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Abbreviations As 2 O 3 : Arsenic Trioxide ATG: autophagy-related proteins, such as ATG1, ATG4, ATG5 ATG7 etc.

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Article CAS PubMed Google Scholar Cao Y, Klionsky DJ. GABARAPs are required for interferon-γ IFNγ -mediated antimicrobial responses through binding to ADP-ribosylation factor 1 ref. Microautophagy was first described in mammalian cells as a process involving the invagination of lysosomal membranes that incorporate cytosolic material into lysosomes, followed by membrane fission and degradation 90 , 91 Fig.

Because observing microautophagy in small lysosomes is difficult by light microscopy, the underlying molecular mechanisms have been primarily revealed in yeasts and plants, where the vacuole is sufficiently large for optical observation. Like macroautophagy, microautophagy can be both non-selective and selective; the process non-selectively enwraps cytosolic material but also selectively recognizes organelles, such as peroxisomes micropexophagy , mitochondria micromitophagy , lipid droplets microlipophagy , a subdomain of the ER microER-phagy , a portion of the nucleus micronucleophagy , and photodamaged chloroplasts microchlorophagy 2 , 92 , Microautophagy requires the ESCRT machinery at the membrane fission step 2.

However, its dependency on ATG proteins is complicated and may differ among cargo types and inducing conditions. While ATG proteins seem to be dispensable in general microautophagy and microER-phagy, at least some of the ATG proteins are required for microlipophagy 94 , 95 , 96 , micropexophagy 97 , 98 , micromitophagy 99 and micronucleophagy , in yeast as well as microchlorophagy in plants Fig.

In mammals, micromitophagy and microlipophagy seem to be independent of ATG proteins , , whereas micronucleophagy mediated by cGAS requires the ATG8 conjugation system for cargo recognition Thus, microautophagy can be roughly divided into two types: ATG-independent and ATG-dependent Fig.

In mammalian cells, multivesicular body formation of endosomes is considered to be a type of microautophagy referred to as endosomal microautophagy Endosomal microautophagy occurs constitutively and is also induced during early periods of amino acid starvation, leading to the degradation of cytosolic proteins, particularly selective macroautophagy adaptors, such as SQSTM1, NDP52, NBR1, TAX1BP1 and NCOA4 an adaptor for ferritin 5 Fig.

The multivesicular body pathway in yeast is also known to be induced by starvation and contributes to early proteome remodelling during starvation 6. Starvation-induced endosomal microautophagy in mammals requires ESCRT-III CHMP4B and VPS4 but not ESCRT-0, -I or -II ref.

The necessity of ATG proteins in this pathway is also complicated. The ATG8 conjugation system is required for the degradation of SQSTM1 and NDP52 and partially required for NBR1 and TAX1BP1 but not for NCOA4, whereas FIP and VPS34 are not required for any of them 5. Therefore, ATG proteins should be important for cargo recognition rather than membrane dynamics in this case Fig.

Endosomal intraluminal vesicles formed by microautophagy are directed to lysosomes for degradation, but they are also secreted to the extracellular space in mammals. Several RNA-binding proteins, including HNRNPK and SAFB, are incorporated into endosomal intraluminal vesicles by the LC3-dependent endosomal microautophagy-like pathway, referred to as LC3-dependent extracellular vesicle loading and secretion LDELS This process differs from canonical endosomal microautophagy in that it is independent of ESCRTs; however, it is dependent on ceramide produced by neutral sphingomyelinase 2 nSMase2, also known as SMPD3 , which is an alternative pathway of endosomal membrane invagination Table 2.

Additionally, in mammals, the ER-phagy receptor SEC62 mediates microER-phagy in an ATG8 binding-dependent manner By contrast, cargo recognition in ATG-independent microautophagy is not well understood.

Specific subdomain formation may be important. For example, in microER-phagy in yeast, the ER membrane forms multilamellar whorls consisting of ribosome-free ER membrane to be subjected to microautophagy In Schizosaccharomyces pombe , microautophagy is used for a biosynthesis pathway for vacuolar enzymes, termed the Nbr1-mediated vacuolar targeting NVT pathway part 2 of Fig.

cerevisiae but uses a different route 8 , This pathway is independent of ATG proteins but requires Nbr1 to recognize its cargos, such as aminopeptidases Ape2, Ape4 and Lap2 and α-mannosidase Ams1. In the NVT pathway, recruitment of Nbr1 to the endosomal membranes is mediated by ubiquitin 8 , in sharp contrast to the process of macroautophagy, in which mammalian NBR1 or its yeast homologue Atg19 is recruited by ATG8.

In mammalian cells, fluid-like ferritin—NCOA4 condensates are subjected to macroautophagy and endosomal microautophagy, both of which require TAX1BP1 for incorporation , Because TAX1BP1 interacts with NCOA4, TAX1BP1 can bridge autophagosomal ATG8 and ferritin—NCOA4 condensates in macroautophagy.

However, the mechanism by which TAX1BP1 mediates the incorporation of ferritin—NCOA4 condensates to endosomes has yet to be elucidated, because it is largely independent of ATG8 ref. HSC70 recognizes the KFERQ-like motif contained in selective cargos and incorporates them into endosomes the KFERQ-like motif was originally identified as a signal for chaperone-mediated autophagy 11 Fig.

In this process, HSC70 binds to PS on the endosomal membrane via its cationic domain and induces inward membrane deformation , This KFERQ-dependent endosomal microautophagy is also conserved in Drosophila , despite its lack of chaperone-mediated autophagy Notably, this pathway requires Atg1 and Atg13, but not Atg5, Atg7 or Atg In LDELS, ATG8 is required for recognizing the LIR sequence of RNA-binding proteins such as HNRNPK and SAFB Membrane invagination occurs even without ATG8 lipidation, but resultant intraluminal vesicles do not contain selective cargos.

How ATG8 translocates to endosomes is unknown. A mechanism similar to LAP may be used. Another issue warranting investigation is why only a subset of microautophagy cargos depend on ATG8 to be recognized in both ESCRT-dependent endosomal microautophagy and LDELS.

Given the crucial roles of autophagy in various physiological processes, including stress responses and intracellular clearance, it has been postulated that autophagy is involved in the pathogenesis of human diseases.

However, it is difficult to determine which diseases are associated with changes in autophagy owing to a lack of methods with which to measure autophagic activity in humans. Nevertheless, recent genetic studies have identified a number of mutations in autophagy-related genes associated with human diseases, suggesting that autophagy alteration contributes to the development of these diseases.

Moreover, studies using acute systemic Atg7 knockout and Fip knockout mice , and brain-rescued systemic Atg5 knockout mice suggest that organs highly susceptible to autophagy deficiency include the nervous system, immune system, liver and intestine.

Consistent with these findings, these tissues are often affected in autophagy-gene-related diseases Tables 3 , 4. In this section, mutations and polymorphisms of genes involved in general and selective autophagy are discussed.

However, it is important to consider that, as emphasized above, most of these autophagy genes also have non-autophagic functions Table 1. Therefore, the identification of mutations in autophagy genes does not directly implicate a defect in canonical autophagy in the disease phenotype.

The involvement of non-autophagic function should always be considered in the interpretation of these mutations. Autophagy-related diseases include Mendelian disorders caused by mutations in autophagy genes Table 3.

The most frequently affected tissue seems to be the nervous system. Homozygous mutations in ATG5 and ATG7 were found to be associated with human neurological diseases , Autophagy is suppressed in these diseases, but only partially, because small amounts of either the ATG12—ATG5 conjugate or LC3-II the lipidated form can be detected.

Patients with these diseases arising from mutations in ATG5 and ATG7 show some overlapping phenotypes, including ataxia and developmental delay. Patients with ATG7 mutations also show abnormal cerebellum and corpus callosum structure and facial dysmorphism it is unknown whether patients with ATG5 mutations have these abnormalities.

SQSTM1 accumulates inpatient-derived cells, confirming reduced autophagic flux , Mutations in the PROPPIN family of proteins also cause neurodegenerative diseases, but their phenotypes are somewhat different.

A homozygous mutation in WIPI2 was found in patients with a complex developmental disorder known as intellectual developmental disorder with short stature and variable skeletal anomalies IDDSSA , , , The detected ValMet mutation reduces WIPI2—ATG16L1 binding and autophagic flux This is a biphasic disease that demonstrates infant-onset, non-progressive psychomotor retardation, epilepsy and autism as well as adolescent-onset dystonia, Parkinsonism and dementia.

Iron accumulation in the globus pallidus and substantia nigra is one of the hallmarks of this disease, but its relationship with ferritinophagy is unclear because iron accumulation has not been reported in other diseases related to autophagy gene mutations. Given that the deletion of either WIPI3 or WIPI4 suppresses autophagy only mildly compared with deletion of WIPI2, ATG5 or ATG7 N.

Mutations in genes related to selective autophagy also cause disease Table 3. Parkin, a ubiquitin ligase, ubiquitinates various proteins in depolarized mitochondria in a PINK1-dependent manner, recruiting autophagy adaptors such as NDP52 ref. Although Parkin- and PINK1-dependent mitophagy is clearly observed in cell culture, its physiological relevance was initially unclear because Prkn or Pink1 knockout mice show almost normal basal mitophagy levels without an obvious phenotype under normal conditions , However, recent studies revealed that aged Prkn knockout mice develop locomotor impairments associated with dopaminergic neuronal loss Intestinal infection could also promote neurodegeneration in Prkn knockout mice Furthermore, Parkin- and PINK1-dependent mitophagy is physiologically important to suppress the release of mitochondrial DNA into the cytosol and subsequent inflammation under stress conditions in vivo , By contrast, another report suggests that PINK1-dependent mitophagy in endothelial cells could be pro-inflammatory via the release of mitochondrial formyl peptides Thus, the pathophysiological role of Parkin- and PINK1-dependent mitophagy may depend on cell type or context.

Mutations in autophagy adaptors such as SQSTM1 ref. Although the diseases listed above are recessive, some exhibit dominant inheritance, which includes amyotrophic lateral sclerosis ALS , frontotemporal dementia FTD these two are often associated and Paget disease of bone.

Autosomal dominant mutations in the selective autophagy-related genes SQSTM1, OPTN and TBK1 are found in association with these diseases Table 4. TBK1 phosphorylates and regulates OPTN, but in addition to this canonical role, TBK1 can also directly recruit the PI3KC3—C1 complex in OPTN-dependent mitophagy Both autosomal recessive and dominant inheritance patterns have been reported in ALS with OPTN mutations The pathogenic effects of these mutations might be mediated by their non-autophagic roles; for example, the TBK1—OPTN axis is also important for the innate immune and RIPK1-dependent cell death pathways However, a gain-of-function hypothesis cannot be entirely excluded.

Of particular interest is that, like other ALS-related proteins , autophagy adaptors such as SQSTM1 refs. Mutations of these genes may exhibit some gain of toxicity. Although most Mendelian disorders associated with autophagy gene mutations are related to the nervous system, there are some diseases involving other tissues and organs Table 3.

An example is Paget disease of bone, which is characterized by one or multiple focal regions with increased bone remodelling. Of its causative genes, SQSTM1 is the major one; however, it remains elusive whether its autophagy adaptor function is involved in the pathogenesis of this disease , The second category includes diseases whose susceptibility is associated with polymorphism of autophagy-related genes Table 4.

Atg16L1 TA knock-in mice exhibit abnormalities in Paneth cells in the intestine and gut microbiota The WD40 repeat domain in ATG16L1 is essential for LAP but not for canonical autophagy 72 ; however, the effect of the TA substitution on autophagy and LAP is relatively small or undetectable , , Autophagy genes such as ATG5 , ATG7 and MAP1LC3B have also been identified as susceptibility genes in autoimmune diseases, including systemic lupus erythematosus SLE Table 4.

This may reflect the role of autophagy in mitochondrial quality control to suppress the release of SLE-inducible damage-associated molecular patterns from mitochondria , In addition to canonical autophagy, these genes are also required for LAP.

Because LAP is important for interferon production in response to the incorporation of DNA-containing immune complexes , the role of autophagy genes in LAP may be related to their genetic association with autoimmune diseases. Association of ATG16L2 with SLE was also identified, but the role of ATG16L2 in LAP is unclear.

Whole-exome sequencing and subsequent missense variant searches in patients with non-alcoholic fatty liver disease revealed an enrichment of the PheLeu and ValAla variants of ATG7 ref.

However, these findings are inconsistent with results obtained in mice showing that a loss of autophagy instead suppresses liver steatosis Thus, partially reduced autophagic activity in humans may have an impact on the liver different from that caused by the complete loss of autophagy observed in autophagy gene knockout mice.

The relationship between autophagy and cancer has attracted much attention. However, although there are numerous reports suggesting the association of specific tumours with autophagy gene single nucleotide polymorphisms, recurrent or driver mutations of core autophagy genes in human cancers are rather rare Thus, autophagy may be still functional in most cancers and could even be important.

In fact, mouse studies have suggested that, while the deletion of autophagy genes might promote tumorigenesis, it also affects tumour growth either through cell-autonomous or -nonautonomous mechanisms Nevertheless, mutations in core ATG genes might be associated with familial cancers. For example, a linkage study identified an association of a germline nonsense mutation of ATG7 c.

In cancer cells, somatic deletion of ATG7 occurs in the complementary allele, leading to complete inhibition of autophagy. This case suggests that autophagy suppression could also be tumorigenic in humans. A quarter century has passed since the first autophagy gene ATG1 , named APG1 initially, was cloned in yeast in ref.

During this period, our understanding of the molecular biology underlying autophagy has grown exponentially. In particular, recent structural biological approaches have provided crucial evidence to explain the unique membrane dynamics of autophagy at the molecular level.

However, despite the increasing clarity of the functions of individual autophagy gene products, several key cell biological questions remain unanswered. For example, what is the mechanism of unidirectional transport of lipids from the ER to autophagosomes?

How is the size of autophagosomes regulated? How is the timing of autophagosome—lysosome fusion regulated? To address these questions, new approaches, including biophysics, theoretical modelling and molecular dynamics simulation, will be useful.

Although we have aimed to summarize the latest knowledge about microautophagy, our efforts may seem incomplete because its mechanisms are still less understood than those of macroautophagy.

It is intriguing that some ATG proteins for example, ATG8 and selective autophagy adaptors for example, NBR1 are used by both macroautophagy and microautophagy.

Whether these molecules exert similar functions in both pathways needs to be elucidated in future studies. In addition, some cargos for example, ferritin are selectively degraded by both pathways, but the regulation mechanisms of sorting remain unknown.

Further research will reveal a more complete picture of autophagy. As we mentioned above, one of the apparent bottlenecks in autophagy research is the lack of methods with which to monitor autophagy in humans. It would be ideal if we could estimate autophagic activity by measuring some metabolites that is, biomarkers in the blood or urine that are secreted via autophagy-dependent pathways.

Alternative techniques may be noninvasive imaging such as fluorescence molecular tomography and positron emission tomography Finally, although many diseases have been found to be linked to autophagy gene mutations or associated with polymorphisms of autophagy genes, the phenotypes of these diseases are diverse.

Thus, it is still difficult to offer a unified explanation of their pathogenesis. This may be due to complementation by homologues, differences in tissue expression and involvement of non-autophagic functions. More investigations will be required to reveal the exact mechanisms by which autophagy gene defects cause a wide range of human diseases.

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