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Selective autophagy in the fight against aging and age-related disordersSslective to the contents of degradation, autophagy can be divided into bulk autophagy non-selective autpphagy and selective autophagy. Bulk autophagy autopuagy non-specific cytoplasmic materials Hyperglycemia and neuropathy response to nutrient Lean muscle mass meal plans while selective autophagy targets selecfive cargoes, such as damaged seldctive, protein Autpohagy, and intracellular pathogens.
Selective autophagy sflective been documented to relate to Stress relief through digital detox reproductive processes, Autopyagy for the spermatogenesis, fertilization, and biosynthesis of testosterone, Autophagy and selective autophagy.
Spermatogenesis is a complex biological process of germ cell anr and differentiation Autophagy and selective autophagy produces a large number of spermatozoa in the autkphagy tubules.
It contains Autophagy and selective autophagy processes: mitosis Anti-ulcer medications spermatogonia, meiosis of Autpphagy, and spermiogenesis, selecitve which round spermatids transform to become the elongated spermatids selsctive 1 ] Aand spermatogenesis, which progresses through precisely timed and highly autpohagy cycles, is seleective to produce spermatozoa continuously and maintain adult male Cayenne pepper spices. In ahtophagy, abnormal spermatogenesis usually results in male abd or infertility [ 2 ].
The fine communication between germ cells and somatic cells within seminiferous tubules autophagg fundamental autophxgy normal spermatogenesis.
Among them, the support and nutritional function of Sertoli cells and Body image confidence boosting function of Leydig cells aurophagy particularly important Autpphagy 3 ] [ 4 ].
Autophagy is a highly conserved catabolic process Metabolism and dieting cell degradation, which is lysosomal swlective and essential for maintaining cellular homeostasis.
The Autophxgy components need to be sequestrated by double-membrane vesicles called autophagosomes, degraded by Positive visualization techniques enzymes seelctive fusing sutophagy lysosomes, and finally complete Lean muscle mass meal plans [ ahd ].
In the aktophagy, autophagy was Autophgay to be non-selective, which is called bulk autophagy. However, an increasing amount of evidence shows that normal Ac levels can seletcive degrade Sdlective proteins and damaged organelles.
Autopahgy main factors involved aktophagy selective autophagy include Auyophagy receptors and adaptor proteins, which connect substrates to autophagy devices.
According to the seldctive substrates, selective autophagy can be divided aitophagy various subcategories, such Autophagy and selective autophagy Autophahy mitophagyliposome lipophagyendoplasmic seleftive reticulophagy wnd, pathogens xenophagyperoxisomes pexophagyselectie ribophagyand aggregated proteins aggrephagy srlective 5 ].
Mitochondrial homeostasis maintained by mitochondrial dynamics and mitophagy is important for the generation Autpohagy energy, cellular homeostasis, steroidogenesis, and regulation of apoptosis [ Aurophagy ].
Of note, selectige is a process that the cell Autolhagy wraps Autophayg degrades damaged or autophaby mitochondria sleective autophagy, thereby maintaining mitochondrial homeostasis [ autkphagy ].
In addition, mitophagy has been implicated in the pathogenesis anc cardiovascular disease and neurodegenerative diseases [ 8 ] [ 9 selctive. When mitochondria are damaged, mitochondria will split, Autophagy and selective autophagy the damaged mitochondrion will be cleared by mitophagy to maintain the normal function of autopjagy mitochondria [ 6 ].
Thus, mitophagy could help to produce a new smaller healthy autphagy that Auto;hagy essential to the recycling of mitochondria zutophagy. Although it has been reported that mitochondria can be degraded by bulk autophagy, the mechanism of mitophagy selectove bulk autophagy is different.
Usually, the mechanisms by which the LC3 adaptor recognizes mitochondrial proteins and Aufophagy mitophagy can be divided Autophhagy ubiquitin-dependent Autopuagy ubiquitin-independent Autpohagy.
Concretely, under normal circumstances, PINK1 can be imported into Autophahy through the translocase of Autiphagy outer green coffee extract supplements TOM and High-protein snacks translocase of the inner membrane Overcoming water retentionso seleective the mitochondrial targeted sequence of PINK1 is selecctive by mitochondrial processing peptidase in the matrix, and PINK1 protein Constant glucose monitoring degraded by protease presenilin-associated rhomboid-like protein PARL on the inner mitochondrial membrane IMM [ 12 ].
In contrast, when mitochondria Lean muscle mass meal plans damaged, since the potential anv the mitochondrial membrane decreases and the mitochondrial Autophagy and selective autophagy depolarizes, Autopyagy can only pass through the Autophaby mitochondrial membrane OMMand PINK1 cannot enter autophaty mitochondria to be degraded.
At this time, Hydration products for athletes accumulates selectjve OMM and selevtive activated by Autopjagy [ 13 ]. The activated PINK1 phosphorylates ubiquitin selectivd Ser65 autolhagy recruit and activate PARKIN ubiquitin seoective activity.
Then, PARKIN produces polyubiquitin Autophgy, which are recognized by ans Autophagy and selective autophagy, including Autopphagy, OPTN, NDP52, TAX1BP1, and NBR1 [ 14 ]. Thus, receptor proteins will recruit mitochondria to the forming autophagosomes for degradation.
Moreover, there are some proteins on the mitochondrial membrane that can directly recognize LC3 and induce mitochondrial autophagy directly, including NIX, BNIP3, FUNDC1, BCL2L13, FKBP8, and NLRX1 [ 15 ]. Among them, NIX and BNIP3 interact with LC3 through their BH3 domain, further inducing mitophagy [ 16 ] [ 17 ]while FUNDC1 directly binds to LC3 to induce mitochondrial autophagy under hypoxic conditions [ 18 ].
BCL2L13, FKBP8, and NLRX1 directly bind to LC3 through their LIR motifs and induce mitophagy [ 19 ] [ 20 ] [ 21 ]. The ubiquitin-dependent and ubiquitin-independent pathways of mitophagy are illustrated in Figure 1. Importantly, it has been shown that defective mitophagy impairs spermatogenesis as discussed below.
Figure 1. Schematic illustration of the ubiquitin-dependent and ubiquitin-independent pathways of mitophagy is shown. A Once mitochondria are damaged, PINK1 will accumulate on the OMM outer mitochondrial membrane and activate it by phosphorylation.
The activated PINK1 recruits and activates PARKIN by phosphorylation. Then, the activated PARKIN produces the polyubiquitin chains recognized by receptors P62, OPTN, NDP52, TAX1BP1, and NBR1.
These receptors will bind with the LC3 adaptor to engulf mitochondria to complete autophagy. B The activated PINK1 recruits ULK1, DFCP1, and WIPI1, which can be recognized by receptors OPTN and NDP52 to induce PINK1-dependent mitophagy.
C Some proteins, including NIX, BNIP3, FUNDC1, BCL2L13, FKBP8, and NLRX1, can directly recognize the LC3 adaptor and initiate the mitophagy process. The lipid droplets LDswhich are mainly made up of cholesteryl ester and triglycerides, are the main lipid storage form in living organisms.
Its degradation can regulate the process of lipid metabolism to provide energy for cells. There are two main catabolic pathways to degrade LDs in response to nutrient limitation: lipolysis and lipophagy [ 22 ]. Lipolysis needs a large number of LD-related lipases to release lipids from LDs, the initiation of which needs adipose triglyceride lipase ATGL [ 23 ].
However, lipophagy, a process that releases fatty acids from LDs by autophagy, has more significant lipophagic activity during starvation compared to lipolysis [ 23 ] [ 24 ].
In addition, lipophagy includes macrolipophagy and microlipophagy. Interestingly, LDs can be recognized as a selective substrate and sequestered by the autophagosome, and degraded by hydrolase after combining with the lysosome, while in microlipophagy in yeast, LDs contact the vacuole lysosome directly with docking sites instead of being engulfed by the autophagosome [ 26 ].
Lipophagy is associated with fatty liver disease, obesity, renal cell carcinoma, and liver cancer cells [ 27 ] [ 28 ]. Furthermore, lipophagy plays an essential role in energy metabolism and lipid homeostasis, and is not only closely related to hepatic diseases but also participates in the regulation of spermatogenesis [ 29 ].
We next focus on the understanding of lipophagy and summarize how lipophagy is involved in the regulation of spermatogenesis. Lipophagy is regulated by many factors, such as Rab GTPase, transcription factors, hormones, and small molecules. For example, small Rab GTPase is involved in the regulation of fat-soluble proteins, and Rab GTPase can be used as a molecular switch cycling between active GTP and inactive GDP [ 30 ].
After nutrient depletion, the small GTPase on the LD surface will activate and switch to an active GTP state [ 31 ]. It is worth mentioning that this activated state will recruit the degradation devices multivesicular bodies and lysosomes to the vicinity of LD and degraded LD by lipophagy [ 32 ].
RAB protein is the most critical member of the Rab GTPase superfamily, and studies have found that Rab protein can affect lipid autophagy and metabolism [ 33 ] [ 34 ]. Among them, RAB7 mainly participates in the process of autophagosomal maturation and intracellular transport [ 33 ] and functions in the fusion of autophagosome membranes and late endocytic membranes with the help of SNARE proteins and HOPS tethering complex [ 35 ].
Besides, it has been well established that RAB10 on the LD surface will be activated during starvation [ 34 ]. Additionally, Rab10 can promote the degradation of LD through lipophagy by interacting with EH-domain-binding protein 1 and membrane-deforming ATPase EHD2 [ 34 ].
Moreover, Rab10 knockdown results in increased LD accumulation in hepatocytes [ 34 ]. Additionally, RAB32 has been shown to co-localize with autophagy markers in Drosophila fat body [ 36 ]. In addition to RAB proteins, transcription factors can be involved in the regulation of lipid metabolism.
For instance, transcriptional factor EB TFEB can induce lipophagy during lipid metabolism via the PPARα Peroxisome proliferator-activated receptor alpha and PGC1α Peroxisome proliferator-activated receptor gamma coactivator 1alpha signaling pathways [ 37 ].
Another transcriptional factor FOXO1 Forkhead box protein O1 can trigger lipophagy by upregulating lysosomal acid lipase LAL and the autophagy gene Atg14 in adipocytes [ 38 ].
In addition, it is well known that the mTOR signaling pathway, which is involved in regulation of autophagy, can inhibit the initiation of autophagy and participate in the regulation of lipophagy as a modulator in response to the change of nutrients and hormones, such as glucose, amino acids, and insulin [ 8 ].
The activity of lipid metabolism and lipophagy will increase in rapamycin mTOR signaling pathway inhibitor -treated hepatocytes [ 39 ]. Interestingly, some small molecules can modulate lipophagy, such as caffeine, tetrandrine, the dietary polyphenol bergamot, and the red wine bioactive resveratrol [ 28 ].
Infertility is defined as failing to achieve a clinical pregnancy after 12 months or more of regular intercourse without contraception [ 40 ].
More and more studies believe that the components of diet and nutrients may be an important factor affecting sperm quality and fertility [ 42 ] [ 43 ]. For instance, diets rich in calories, trans-fatty acids TFAssaturated fats, or cholesterol have a harmful role in spermatogenesis and male fertility [ 44 ] [ 45 ] [ 46 ].
These bad diet habits often lead to obesity, related to impaired fertility [ 47 ] [ 48 ]. Previous studies have demonstrated that autophagy was increased in obese individuals by feeding a high-fat diet HFD [ 49 ] [ 50 ]. They found that the level of autophagy increased in HFD mice, and spermatogenesis and male fertility were also disrupted in HFD mice.
To know the correlation between autophagy and spermatogenesis deficiency in HFD mice, they inhibited and induced autophagy by injecting CQ and RAP intraperitoneally. They found that HFD mice subjected to CQ, an inhibitor of autophagy, showed improved spermatogenesis and decreased infertility. Simultaneously, autophagy was also overactivated in sperm samples from obese subfertile male patients [ 51 ].
Inhibition of excessive autophagy could protect against HFD-induced spermatogenesis deficiency and male infertility. This can provide a new clinical therapeutic method for increasing semen quality and male infertility. Encyclopedia Scholarly Community. Entry Journal Book Video Image About Entry Entry Video Image.
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Lv, C. Selective Autophagy. Lv C, Wang X, Guo Y, Yuan S. Accessed February 15, Lv, Chunyu, Xiaoli Wang, Ying Guo, Shuiqiao Yuan. In Encyclopedia. Lv, Chunyu, et al. Copy Citation. Home Entry Topic Review Current: Selective Autophagy.
: Autophagy and selective autophagy| What is Selective autophagy? | MBL Life Science -JAPAN- | Xutophagy, A. Article CAS PubMed Google Scholar Auotphagy, B. The TBK1 adaptor and autophagy Autophagy and selective autophagy NDP52 restricts the proliferation of swlective bacteria. Structural Dairy-free alternatives Lean muscle mass meal plans analysis of the GABARAP interaction motif GIM. However, loss of FAMB promotes the expansion of ER, leading to ER stress. Cell Host Microbe — Article PubMed CAS Google Scholar Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT et al Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositolkinase complex. |
| Cargo recognition and degradation by selective autophagy | Nature Cell Biology | CellHerbal energy shots One of these adaptor proteins is Autophagy and selective autophagy To Auhophagy and think about natural products and derivatives, small molecule compounds, complexes, combination drugs and functional reorientation of drugs, and further develop more selective and effective anticancer drugs targeting selective autophagy. Jo, C. Cell 7— |
| Selective Autophagy and Cancer | Maio, Aurophagy. Kristensen, A. Cue5 is specifically Autophagy and selective autophagy for proteaphagy of annd or genetically inactivated proteasomes, but does not play a role in starvation-induced proteaphagy Marshall et al. PINK1 is degraded through the N-end rule pathway. Email address Sign up. Article PubMed Google Scholar Zhang, H. París-Coderch L, Soriano A, Jiménez C, Erazo T, Muñoz-Guardiola P, Masanas M, et al. |
Autophagy and selective autophagy -
Parkin ubiquitinates NIX, which facilitates the selective autophagy adapter neighbor of BRCA1 gene 1 NBR1 targeting. FUNDC1, an OMM protein, is a receptor for hypoxia-induced mitophagy [ 36 ].
It has an LIR at the N-terminus, and changes to the LIR motif affect how FUNDC1 interacts with LC3 and how mitophagy is induced [ 37 ]. FUNDC1 is downregulated in a ubiquitin-proteasome-dependent manner under hypoxia as a result of MARCH5-mediated ubiquitination of FUNDC1 at Lys Like Atg32 in yeast cells, FUNDC1 is controlled by phosphorylating and dephosphorylating Ser13 and Tyr18, which are situated close to the LIR motif, during mitophagy.
Under the hypoxic condition, inactivated serine results in an inhibited phosphorylation of Tyr18, which stabilizes the FUNDC1-LC3 interaction, and promotes mitophagosome formation [ 37 ].
PGAM family member 5 PGAM5 promotes mitophagy by dephosphorylating Ser13 and enhancing the FUNDC1-LC3 interaction [ 39 ]. Unc like autophagy activating kinase 1 ULK1 is induced by hypoxia or mitochondrial depolarization, and it is directed towards the mitochondria where it phosphorylates FUNDC1 at Ser17 near the LIR motif and stabilizes its association with LC3, This process accelerates mitophagy [ 40 ].
Under hypoxia, BCL2L1 is degraded and PGAM5 is released, which promotes Ser13 dephosphorylation and thus initiates FUNDC1-mediated autophagy.
Thus, the BCL2L1-PGAM5-FUNDC1 axis plays a key role in response to hypoxia-induced autophagy [ 41 ]. SMURF1 is a homolog of the E6-AP carboxyl terminus HECT and a ubiquitin-like ligase that is primarily involved in the ubiquitination and breakdown of intracellular Smad proteins as well as the control of osteoblast activity [ 18 ].
SMURF1 initiates mitophagy by interacting with autophagosomes through the C2 domain [ 42 ]. Knockdown of SMURF1 significantly inhibits CCCP-induced mitophagy, without affecting the non-selective autophagy.
It is discovered that the C2 domain is necessary for SMURF1-mediated mitophagy but that ubiquitin ligase activity is not. It is suggested that SMURF1 interacts with autophagosomes through the C2 domain [ 42 ].
There are additional proteins and receptors that are in charge of mediating mitophagy in addition to the aforementioned processes for its initiation. An IMM protein called prohibitin 2 PHB2 controls the IMM protease PARL and stops it from cleaving PGAM5.
The unaltered PGAM5 can further stabilize PINK1 to recruit Parkin and other mitochondrial receptors like NDP52, thus promoting mitophagy [ 5 ]. In addition, Mitophagy is induced by BCL2L13 through a mechanism that is not dependent on Parkin [ 43 ].
BCL2L13 localizes on the OMM and directly binds to LC3 through the LIR motif to start mitophagy. A crucial modulator of cellular redox balance, NRF2 may also have an impact on mitochondrial activity. NRF2 protects mitochondrial metabolism by enhancing the stability of mitophagy via counteracting the Warburg effect Fig.
Parkin-independent pathway of mitophagy. The OMM contains a variety of proteins, including BNIP3, BNIP3L, FUNDC1, BCL2L13, FKBP8 and PHB2 as well as other autophagy receptors with LIR motifs that are not subject to ubiquitination.
Direct binding of lipidized LC3 and GABARAP family members on the phagosome membrane initiates mitophagy. ER is a tunnel system surrounded by membrane in cells, which is a crucial organelle found in cells. Sheets and tubules make up the structural components of the ER.
The ER can be classified into two distinct categories: rough ER and smooth ER. The rough ER is also called the granular ER, ribosomes attached to the surface of the rough ER are the site of protein synthesis.
The rough ER serves both as a transport channel for newly synthesized proteins and as a scaffold for ribosome attachment. Smooth ER is also known as non-granular ER.
The cyst wall of the smooth ER has a smooth surface and no ribosome attachment. Therefore, smooth ER is not related to protein synthesis, but its function is more complex. It may be involved in the synthesis of glycogen and lipids, the synthesis of steroid hormones, and secretion [ 45 ].
The ER is a essential organelle for signal transduction and cellular metabolism. ER stress is brought on by misfolded proteins and aggregates that build up in the ER lumen under stressful or unfavorable circumstances. ER stress activates two key quality-control mechanisms: ER-associated degradation ERAD and the unfolded protein response UPR [ 46 ].
The ubiquitin-proteasome system then carries out the degradation of misfolded proteins in the cytoplasm. In order to reduce overall translation, the PERK-eIF2 signaling pathway is activated when UPR induces a variety of regulatory molecules that detect the increase of gathered and unfolded proteins in the lumen.
Additionally, PERK-eIF2α signaling can activate the transcription of genes involved in the ER stress response and maintain the homeostasis and health of the ER.
Excessive ER fragments are broken down by ER-phagy, which is triggered by the buildup of aggregated or misfolded proteins in the ER lumen. At present, a total of 11 ER-phagy receptors have been reported, including Atg39 and Atg40 in yeasts, and FAMB, RTN3L, SEC62, CCPG1, ATL3, testis-expressed protein TEX , calcium-binding and coiled-coil domain-containing protein 1 CALCOCO1 , CDK5 regulatory subunit-associated protein 3 C53 and ER-phagy receptor 1 Epr1 in mammals.
ER-phagy receptors are dispersed throughout several areas and are active in various ER-derived compartments. FAMB is positioned on ER sheets in mammalian cells, where it mediates ER sheet disintegration. The tubular ER is the location of RTN3L, TEX, and ATL3, which are in charge of their degradation.
Atg39 is found on the perinuclear ER pnER in budding yeast cells. Atg40 is primarily found in cytoplasmic ER and cortical ER. Fission yeast cells include the soluble ER-phagy receptor Epr1, whose role is comparable to that of CALCOCO1 in humans. A soluble ER-phagy receptor called C53 is present in both plant and human cells Fig.
The endoplasmic subdomain and the autophagy mechanism are connected in this way. The isolation membrane connects to the ER assembles and expands into phagocytes. The phagosome then encapsulate the ER fragment and seal to form autophagosome.
The autophagosome and lysosome then combine to produce a vacuole in yeast and plants, or an autolysosome in mammalian cells. The first discovered ER-phagy receptor is FAMB, sometimes referred to as RETREG1 or JK1.
It is only functional throughout the ER-phagy phase, and knockdown of FAMB does not significantly influence other types of selective autophagy and macroautophagy [ 48 ]. However, loss of FAMB promotes the expansion of ER, leading to ER stress.
On the contrary, overexpression of FAMB causes the rupture of endoplasmic reticulum membranes MAMs and the formation of autophagosomes [ 49 ]. Structurally, FAMB is an intramembrane protein located on the ER sheets.
The reticular homeodomain RHD at the N-terminus of FAMB promotes its fixation to MAMs, thereby inducing MAMs remodeling and bending. For ER fragmentation, FAMB oligomerization is essential.
ATL2 is a GTPases present in ER, which may mediate the clearance of impaired ER downstream of FAMB. RTN3 is concentrated in highly tortuous MAMs, particularly in the tubular ER. It belongs to the family of reticulons, consisting of RTN1—4 that share a highly homologous RHD but different N-terminal domains [ 51 , 52 ].
Only RTN3L performs the biological activity of the ER-phagy receptor, which interacts with all 6 Atg8 family members in mammals, with GABARAP-L1 as the preferable one. The RHD at the C-terminus of GABARAP-L1 assists the anchoring of RTN3L on the ER and the bending of MAMs, and the 6 functional LIR motifs at the N-terminus form dimers that break down ER tubules into discrete fragments and transport to lysosomes [ 53 , 54 ].
SEC62 is located on ER sheets and tubules. SEC61, a crucial part of the translocon, is bound by the ER membrane proteins SEC62 and SEC Then, newly created polypeptides are transported to the rough ER [ 55 ]. Serving as an ER-phagy receptor in mammal cells, SEC62 maintains the homeostasis of ER by degrading excessive ER via triggering UPR, which is known as a process of ER remodeling or ER re-shaping.
A LIR motif in the cytoplasm of C-terminus of SEC62 connects LC3 on the autophagosome membrane, thereby promoting the transition of autophagosomes toward the lysosomes.
CCPG1 has a role in the phagocytic destruction of ER tubules and is mostly found on the tubular ER. It consists of an N-terminus in the cytoplasm, a C-terminus and a transmembrane domain attached to the ER membrane.
In CCPG1-deficient cells, nutrient deprivation-induced ER phagocytosis impairs the RTN3-mediated tubular ER fragmentation mechanism, indicating a synergistic effect of CCPG1 and RTN3 [ 58 ]. ATL3 is a member of the dynamin-like, integral membrane GTPase that is located on the tubular ER and induces the tubular ER-phagy.
It includes two transmembrane helices that are tightly spaced apart and joined by a luminal polypeptide. The trans-dimerization of a GTPase domain located at the N-terminus causes the tubular ER to fuse.
Two GIMs found in ATL3 target the tubular ER for lysosomal degradation by binding to GABARAP proteins [ 59 ]. A synergistic effect of ATL3 and RTN3L has been reported. In ATL3-deficient cells, RTN3L is overexpressed to compensate for the ER-phagy dysfunction, and vice versa.
It is suggested that ATL3 exerts a dual function in ER-phagy, which not only recruits the ULK1 complex to initiate the function of phagosomes, but also induces ER fragmentation by binding to GABARAP and targets autophagosomes.
TEX is a single-pass transmembrane ER protein, with the N-terminus and C-terminus in the lumen of the ER and the cytoplasm, respectively.
It contains a LIR and an unstructured intrinsically disordered region IDR. TEX exerts a vital role in ER-phagy [ 61 ]. Atg39 is an ER-phagy receptor in the S. cerevisiae , which is localized on the pnER and served as a component of the nuclear membrane. It contains a transmembrane domain and an AIM in the cytoplasmic N-terminus.
Atg39 serves a similar receptor role to that of CCPG1 in mammals [ 62 ]. Atg40 is a putative yeast homologue of FAMB that is localized on the cER and cytoER. It is responsible for the degradation of excessive cER and cytoER in the S. Silence of Atg40 greatly blocks ER-phagy, which can be almost entirely inhibited by co-silence of Atg39 [ 62 ].
CALCOCO1, unlike other ER-autophagy receptors, is ER peripherally associated and is defined as a soluble ER-phagy receptor. Instead of the localization on the MAMs, CALCOCO1 targets the ER interaction with VAMP-associated proteins VAPA and VAPB on the ER membrane via a conserved fatty acid-like motif [ 63 ].
An atypical LIR motif LVV at the N-terminus of CALCOCO1 induces ER-phagy via binding to Atg8 family members, especially the GABARAP subfamily; whereas the C-terminus of CALCOCO1 has a UDS interface region UIR that can connect to UDS and help LVV bind to Atg8 family members [ 64 ].
C53 is a cytoplasmic protein that is specifically recruited to autophagosomes in plant and mammalian cells in response to ER stress [ 65 ].
ER stress stimulates the recruitment of C53 to the ER by vesicle transportation. Epr1 can mediate dithiothreitol DTT -induced ER-phagy. It is a soluble protein with an AIM motif and a FFAT motif in the IDR at the C-terminus.
Epr1 interacts with Scs2 and Scs22, two VAPs that are present in the ER, to localize to the ER. The AIM motif attracts Atg8 to the ER during ER-phagy [ 66 ].
A crucial stage of the immune response is called xenophagy, which is a process of selective autophagy used to destroy intracellular invaders like viruses, bacteria, and fungus.
By facilitating xenophagy, bacterial infection can encourage inflammation-mediated carcinogenesis [ 67 , 68 ]. Normal physiological conditions result in a balance between variables that promote and inhibit inflammation.
A subtle interference in the inflammatory factors or a chronic inflammation caused by the long-term infections eventually causes carcinogenesis [ 69 ].
Through recognizing, engulfing and degrading pathogens, xenophagy lowers intracellular pathogens. Thus, it is anticipated that xenophagy will serve as a cancer preventive strategy Fig.
Xenophagy is a way of capturing pathogens. A Xenophagy captures bacteria: Ubiquitin recognizes cytoplasmic bacteria and binds to the Xenophagy adaptor protein and autophagosome membrane protein LC3. The autophagosome-containing bacteria then combines with the lysosome to breakdown.
B Xenophagy captures the virus. The autophagosome recognizes intact viruses or virus particles, and the subsequently captures virus replicates in the autophagosome and avoids fusing with the lysosome.
The role of xenophagy differs from types of bacteria. Xenophagy fights against the invasion of Streptococcus pyogenes , serving as an innate defense system [ 70 ].
Early on in a Salmonella typhimurium infection, they are exposed to the cytosol within damaged vacuoles, when they are identified and targeted by heterologous autophagy. Thus it is able to prevent bacterial colonization in the cytoplasm [ 71 ]. Xenophagy exerts a protective role by inhibiting the infection of Mycobacterium tuberculosis [ 72 , 73 ].
Lipids are naturally-occurring molecules that serve as energy supplies, signaling molecules and substrates for biological functions. Triglycerides TG , steroids, and phospholipids are the three forms of lipids [ 74 ]. Triacylglycerol TAG is the correct chemical name of TG, often referred to as fat, this is the primary lipid storage or carrier.
TG is usually used for food intake and lipogenesis. TG is mostly synthesized in the liver and saved in lipid droplets LDs.
The hydrolysis and metabolism of TG differ from the different parts of the body with varying fat contents. Lipid accumulation may lead to lipotoxicity, impair autophagy and lysosomal function, and thus causing diseases, metabolic syndromes or even cell death.
Lipophagy is a process of selective autophagy for degrading intracellular cholesterol and TG stored in LDs via the lysosomal acid lipase, which contributes to maintain the cellular lipid homeostasis by continuously recycling and re-distributing lipids [ 77 ].
In lipophagy, lysosomal lipase is expressed by Transcription factor EB TFEB , a major transcription factor that regulates the transcription of genes involved in multiple biological pathways and is involved in important cellular functions [ 78 ].
These include autophagy, lysosomal biogenesis, lysosomal exocytosis, lipid metabolism, and mitochondrial biogenesis [ 79 , 80 , 81 ]. TFEB is positively correlated with the gene expression changes of autophagy genes and the relative lipidation of autophagy marker LC3. TFEB is an effective target to regulate autophagy and lysosomal activity, which can successfully combat different pathological conditions including cancer [ 82 ].
Therefore, its anti-cancer effect is worth further exploration. The receptors responsible for mediating lipid autophagy have long been a mystery, but a study by Zheng Wang et al. has filled this gap by showing that ORP8, a member of the oxysterol binding protein OSBP family, can act as a receptor mediating adipoautophagy [ 83 , 84 ].
It is reported that the perilipin family [ 85 , 86 , 87 ], and Rab GTPases are closely linked with lipophagy, although the underlying mechanisms require to be further explored Fig. Overview of the major proteins of lipophagy. In lipolysis, TG is first hydrolyzed by adipose triglyceride lipase ATGL to generate diacylglycerol DG.
DG is then hydrolyzed by Hormone-sensitive lipase HSL to generate monoacylglycerol MG , while HSL is phosphorylated by proteins surrounding lipid droplets. Finally, MG is hydrolyzed by Monoacylglycerol lipase MGL to yield glycerol and free fatty acids. Lipohagy is defined as selective autophagy degradation of LDs.
In the state of nutritional starvation, lipophagy cells are formed, which are composed of Atg5, Atg7, LC3 and Rab families. The PNPLA family has specific molecular motifs associated with LDs and plays a crucial role in LDs decomposition.
Autophagosome phagocytes LDs and fuses with lysosome to form autophagosome. The lysosomal lipase expressed by TFEB then hydrolyzes the neutral lipids in LDs. Lysosomes are major degradative organelles that degrade materials by endocytosis, phagocytosis and autophagy.
Lysosomes are essential for maintaining cellular homeostasis, promoting cell growth, and performing immune defense functions [ 91 ]. The endosomal sorting complexes needed for transport ESCRT machinery can restore the integrity of lysosomal membranes when drugs and stimuli damage them.
However, severely damaged lysosomes are cleared through a selective macroautophagic process, that is, lysophagy. Lysosomal membrane permeabilization LMP , or complete disruption of lysosomes, is a ordinary and serious stress associated with degenerative diseases, infections, and cancers.
Next, the ubiquitinated protein attracts autophagy aptamers to trigger autophagy, including phospholipase A 2-activating protein PLAA , valosin-containing protein VCP , TAXBP-1, and SQSTM1. Galectins can also keep an eye on how the lysosomal membrane degrades and how autophagy is cleared as a result.
Galactose-bound lectins are usually found in the cytoplasm and nucleus, but carbohydrate chains containing galactose are widely distributed on the cell surface and on the lumen side of the endosome, lysosome, and Golgi apparatus [ 92 ].
Once lysosomes are permeabilized, the binding of galectin-1 Gal-1 , galectin-3 Gal-3 , galectin-8 Gal-8 and galectin-9 Gal-9 to exposed β-galactosides on the inner membrane occurs and then triggers the downstream signaling pathways [ 93 ].
A synergistic effect of galectins is considered to induce lysophagy. They are able to sensitize damaged organelles, and then ubiquitin-conjugating enzyme E2Q-like protein 1 UBE2QL1 labels lysosomal membrane proteins using K48 ubiquitin chains.
K63 ubiquitination, p62 recruitment, and binding of LC3-associated phagocytosis are accomplished by an unknown method Fig. Lysophagy: Removal of damaged lysosomes by autophagy. TRIM16, UBE2QL1, SCF FBXO27 , LRSAM1, and other lysosomal autophagy factors are brought in to ubiquitinate lysosomal membrane proteins in the event of lysosomal membrane injury or even in normal circumstances.
Autophagy adapters are then recruited to induce autophagy. Galectin-3 is normally present in the cytoplasm and nucleus but can be attracted to disrupted lysosomes in the case of lysosomal damage. Phagosome formation is triggered by the assembly of autophagy initiation proteins, which is made possible by the TRIMGalectin-3 complex.
On the other hand, Galectin-8 recruits LC3-positive phagocytes to mediate lysophagy by directly binding to the autophagy receptor NDP52, independent of ubiquitin. Important metabolic enzymes for bile acid production, fatty acid β-oxidation FAO , purine catabolism, and ether phospholipid formation are peroxisomes.
They are also important redox-regulated organelles because of the dual-function of generating and scavenging reactive nitrogen species RNS and ROS. Therefore, maintaining proper size, number and function of peroxisomes by regulating their biogenesis and degradation is of great significance to keep homeostasis [ 95 ].
It has been established that a number of additional proteins and genes, including peroxin PEX and dynein-related protein 1 Drp1 , are involved in the control of peroxisome formation and division.
Like other forms of selective autophagy, pexophagy necessitates certain adapters and receptors. An adapter translocates to the peroxisome membrane and links peroxidase to the autophagosome, thus inducing pexophagy.
pastoris , Atg36, NBR1 and p62 in S. cerevisiae , and acyl-CoA-binding domain containing protein 5 ACBD5 in mammals [ 92 ]. pastoris is a widely used model in the research of pexophagy.
Atg30 is localized on the peroxisome membrane, which is transiently translocated to pre-autophagosomal structures PAS during the process of pexophagy. By assembling the pexophagic receptor-protein complex RPC , it regulates pexophagy.
Pexophagy is induced by overexpression of Atg30, and Atg30 phosphorylation requires peroxisomal biogenesis factor 3 PEX3 [ 96 ]. Positive regulation of RPC assembly is provided by Atg37 and ACBD5 [ 97 ]. Atg30 selectively destroys peroxisomes through interactions between Atg8 and Atg11 and RPCs, this process is dependent on PEX3 and Atg Atg37 and PEX3 can regulate HRR25 positively and negatively, respectively.
Because Atg37 also serves as an acyl-CoA binding protein ACBP , acyl-CoA influences the interaction between Atg30 and Atg37, which in turn influences how Atg11 is recruited to RPC [ 98 ].
A ubiquitin ligase called PEX2 is involved in the mammalian process of pexophagy. It induces peroxisome ubiquitination and pexophagy in a way that is NBR1 dependent.
Normally, mTORC1 maintains a low level of PEX2 via the ubiquitin-proteasome pathway [ 99 ], which also ensures that the peroxisomal membrane is recycled for ubiquitinated PEX5.
Amino acid starvation induction upregulates PEX2, and subsequently, ubiquitinated PEX5 and kDa peroxisomal membrane protein PMP70 are degraded via pexophagy via the recruited NBR1 Fig.
Overview of the major proteins of Pexophagy. Under normal circumstances, the mTORC1-mediated proteasome pathway can maintain low PEX2 expression levels.
Under starvation conditions, an increase in PEX2 causes PEX5 and PMP70 to get ubiquitinated, which ultimately triggers Pexophagy in an NBR1-dependent way. USP30 offsets PEX2 by deubiquitinating its substrate to prevent Pexophagy. TSC2 is induced by activated ATM kinase, and mTORC1 is inhibited by activated TSC2.
Additionally, ATM phosphorylates PEX5 at Ser, which causes PEX5 to be ubiquitinated at Lys The proteophage target of ubiquitin-dependent peroxisome is monobititinated PEX5 on Cys PEX1 and PEX6, which are affixed to the peroxisome by PEX26, will ubiquitinate PEX5 and remove it from the membrane after transit.
Thus far, ACBD5 is the sole protein that is specific to phagocytic cells. Recruitment of Pexophagy-specific receptors or adapters may be facilitated by ACBD5. So far, 25 kinds of selective autophagy have been identified [ ].
Besides the abovementioned selective autophagy, the role of novel types like nucleophagy and ferritinophagy in cancers has been gradually concerned.
Nucleophagy is responsible for maintaining the nuclear integrity and genome stability during the early stages of carcinogenesis by eliminating problematic genetic materials. However, in the advanced stage, nucleophagy is favorable to cancer cell survival and metastasis [ ].
It is reported that a cytosolic iron chaperone poly rC -binding protein 1 PCBP1 negatively mediates ferritinophagy-induced ferroptosis by impairing the stability of BECN1 mRNA.
Therefore, silencing PCBP1 is a potential therapeutic strategy for killing ferriphilic refractory cancer cells via enhancing the susceptibility to ferroptosis [ ].
Moreover, studies have shown that Ubiquitin-specific peptidase 8 USP8 plays an important role in regulating ferritinophagy and ferroptotic responses in cancer cells, revealing that USP8 could be a viable target for cancer therapies using ferroptosis [ ].
Even if there are more and more forms of selective autophagy, the mechanism behind them is still unclear, posing a huge challenge on clinical research.
Carcinogenesis can be inhibited or promoted by autophagy, making it a double-edged sword. It prevents cancer cell proliferation and stabilizes the genome by degrading damaged organelles in cancer cells during the process of carcinogenesis and malignant transformation.
However, in the malignant microenvironment, autophagy is essential for cancer development and progression to provide energy and nutrients [ ].
A defining feature of the tumor microenvironment, hypoxia can accelerate the spread of cancer. In the initial stage of carcinogenesis, a microenvironment formed by rapidly proliferating cancer cells and local hypoxia and nutrient deficiency causes mitochondrial dysfunction and thus induces mitophagy.
Cancer cells need a demand of more nutrients, and mitophagy provides amino acids for cell growth via recycling from lysosomes. Mitophagy not only provides nutrients for ATP production and biogenesis, but also satisfies metabolic needs of cancer cells by degrading carbohydrates, proteins, lipids and nucleotides [ ].
In order to maintain uncontrolled growth rates, cancer cells employ unconventional mechanisms to obtain energy from the outside world. Due to mitochondrial dysfunction, mitochondrial oxidative phosphorylation OXPHOS is inhibited in cancer cells. This reprogramming of energy metabolism is known as the Warburg effect [ ].
Mitosis promotes the glycolytic pathway and reduces the use of OXPHOS mechanism, which facilitates OXPHOS to meet the rapidly increasing energy demand. Mitochondrial OXPHOS and glycolysis act synergistically to maintain the balance of energy metabolism in cancer cells [ ].
Additionally, mitophagy can inhibit the production of ROS and an ineffective consumption of valuable nutrients like oxygen, which promotes the fast growth of cancer cells Fig. Mitophagy provides sufficient nutrition, energy and oxygen for cancer cells. The Warburg effect is the process by which glycolysis-a process that converts glucose into lactic acid-is promote by mitophagy.
Mitochondrial OXPHOS and glycolysis act in concert to maintain the balance of energy metabolism in cancer cells. Similarly, PINK1 absence can cause the Warburg effect by lowering Pyruvate kinase M2 PKM2 activity and stabilizing HIF1a, which keeps cancer cells proliferating quickly.
PKM2 is one of the key enzymes in glycolysis, and reducing PKM2 activity can promote the rapid proliferation of cancer cells by stimulating the pentose phosphate pathway. HIF1a transcription is up-regulated, initiating glycolytic metabolism, and its target genes are expressed more, which controls mitophagy.
Hypoxia stimulation and the increase and elevation of mitochondrial ROS also cause these effects. Mitophagy is crucial for maintaining the stem cell features of CSCs [ ]. Through switching from OXPHOS to glycolysis, essential properties of CSCs are maintained, including stem cell self-renewal and cancer growth.
To satisfy the energy requirements, a metabolic remodeling of CSCs is achieved via mitophagy, which stimulates metabolic reprogramming, the acquirement of the glycolytic or OXPHOS phenotype, and the progression of cancer Fig.
The dual role of Mitophagy in cancer. On the one hand, mitophagy can promote cancer by providing adequate nutrition, energy and oxygen to cancer cells, maintaining the stem cell characteristics of tumor stem cells, promoting the invasion and metastasis of cancer cells, mediating drug resistance of cancer cells, inhibiting iron death, and activating inflammasome.
On the other hand, mitophagy at the basal level can degrade dysfunctional mitochondria to maintain cell homeostasis, limit the production of ROS and thus inhibit cancer.
And excessive mitophagy and mitophagy after chemotherapy can also promote cancer death. In order to prevent metastasis, when anchorage-dependent cells split out from the extracellular matrix around them, apoptosis takes place.
This process is known as anoikis [ ]. The capacity to resist anoikis has been evolved by cancer cells with malignant potential, thus being survived after detaching the primary lesion and metastasizing through the lymphatic or circulatory system.
There is mounting evidence that mitophagy protects cancer cells against anoikis. Additionally, mitophagy reduces the possibility of apoptosis by maintaining mitochondrial functions such as ATP synthesis, antioxidant defense, and prevention of DNA damage and energy balance Fig.
Cancer cells can induce resistance through mitophagy. It is reported that mitophagy activates autophagy in the neuroblastoma cell line SH-N-AS, thus enhancing the resistance to the anti-cancer agent UNBS [ ]. A comprehensive understanding of tumor-related signaling pathways and the physiological functions of autophagy is expected to open up new possibilities for the treatment of tumor drug resistance and the improvement of clinical outcomes [ ] Fig.
Ferroptosis is a type of programmed cell death characterized by the dependence on irons and accumulation of lipid peroxides [ ]. It is suggested that mitophagy helps cancer cells survive by preventing ferroptosis via activating Nrf2. Nevertheless, the exact interaction between mitophagy and ferroptosis has not been fully elucidated Fig.
It is validated that mitophagy exerts its biological role in cancers through activating the inflammasomes [ ]. During the process of mitophagy, the deficiency of PINK1 and PARK2 activates the AIM2 inflammasome and thus accelerates the aggravation of pancreatic cancer [ ].
In mitophagy receptor FUNDC1-deficient hepatocytes, the accumulation of dysfunctional mitochondria causes the activation of inflammasomes, overproduction of IL-1β and hyperproliferation of hepatocytes [ ]. Therefore, carcinogenesis may be influenced by inflammasome activation and mitochondrial homeostasis abnormalities Fig.
Mitophagy is also thought to be an anti-tumor mechanism [ ]. Mitophagy is suppressed and damaged mitochondria aggregate as a result of some genes dysfunction. This promotes the development of tumors. Growing data from numerous studies lends credence to the idea that adaptor proteins, or certain mitotic receptors, function as tumor suppressors in cancer.
In mice, Parkin or PINK1 deletion promotes KRAS-driven pancreatic carcinogenesis [ ] and results in the development of hepatocellular carcinoma [ ]. In humans, Parkin deletion has been found in tumors including colorectal cancer [ ], glioblastoma [ 27 ], melanoma [ ], lung cancer [ ], and breast cancer [ ].
Increased pro-inflammatory signaling, genomic instability [ ], and increased cancer cell proliferation and resisitance to apoptosis [ ] are all caused by parkin deletion.
Due to the buildup of mitochondrial malfunction brought on by Parkin loss, ROS generation, glycolysis, and mitochondrial OXPHOS are all increased. This may contribute to the Warburg effect and hence encourage the growth of malignancies Fig.
Under the normal circumstance, mitophagy is a defensive mechanism to protect cells through degrading damaged mitochondria. Nevertheless, an excessive mitophagy results in the abnormal mitochondrial cycle and energy metabolism disturbance, finally leading to cell death. Hypoxia-inducible factor 1-alpha HIF1A , which is activated by the growth of cancer cells, causes hypoxia and upregulates BNIP3.
Pro-apoptotic molecule BNIP3 promote mitophagy, which inhibits the fusing of damaged mitochondria [ ]. It is reported that ceramide-induced the upregulation of BNIP3 in glioma cells, which further activates mitophagy and causes cancer cell death Fig.
An excessive mitophagy causes the type II programmed cell death. Existing evidences have shown that one of the main mechanisms behind cancer cell death is autophagy-dependent cell death.
After chemotherapy, mitophagy contributes to inhibit the progression of cancers by accelerating cancer cell death [ ]. Emeric Limagne et al. found that Adding a MEK inhibitors to pemetrexed-cisplatin can promotes mitophagy, thereby restoring the efficacy of chemoimmunotherapy in cancer treatment [ ].
Mohammed Dany et al. found that LCL reduced resistance to the anti-acute myeloid leukemia drug crenolanib by inducing mitophagy [ ]. It is concluded that triggering mitophagy in cancer cells may be useful anti-cancer treatment Fig.
In carcinogenesis, ER-phagy plays a complicated role. Because ER-phagy lessens excessive stress in the ER, cancer cells are better equipped to proliferate and survive. On the contrary, ER-phagy is also an anti-cancer mechanism to induce cancer cell death. The exact role of ER-phagy in cancers depends on the cancer types, stage of progression and the microenvironment [ ].
There are two roles for FAMB in cancer. Firstly, Cancer growth may be aided by FAMB-mediated ER-phagy. FAMB acts as a tumor promoter in esophageal squamous cell carcinoma and hepatocellular carcinoma [ , ].
Another study on colorectal cancer found that ER-phagy mediated by FAMB can reduce UPR induced by treatment drug brigatinib, thus promoting the survival of cancer cells, while knockdown of FAMB can increase the sensitivity of colorectal cancer to brigatinib [ 6 ].
High levels of SEC62 expression have been associated with increased resistance to UPR and other endoplasmic reticulum stress in non-small cell lung cancer and thyroid cancer cells, which facilitates cancer cell invasion and migration [ ]. Thyroid, prostate, and NSCLC cancer cells were more susceptible to ER stress brought on by thapsigargin after SEC62 expression was inhibited.
In HeLa cells, suppressing SEC62 likewise stops the cells from migrating. These combined observations imply that SECmediated ER-phagy may aid cancer cells in better coping with endoplasmic reticulum stress and aid in their survival and migration [ ].
According to earlier studies, the N-terminal R12H of CALCOCO1 is associated with colorectal cancer metastasis and breast cancer development [ , ]. The N-terminal R12H mutation of CALCOCO1 reduces the interaction between CALCOC1 and LC3C. Consequently, CALCOCO1 mutation-induced ER-phagy deficiency may be associated with the development of breast cancer [ ].
By controlling the key tumor suppressors p53 and CDK1 cyclin B1 [ ], the development of cancer cells is inhibited by C On the other hand, it has also been demonstrated that significant levels of C53 expression are present in hepatocellular carcinoma cell lines, indicating that this protein may be involved in promoting tumor invasion and metastasis [ ].
When protein translation is obstructed, ER stress can be responded by ER-phagy mediated by C Thus, we hypothesized that C53 helps cancer cells survive ER stress by upregulating ER autophagy [ ]. Autophagic cell death can be caused by excessive ER-phagy in cancer cells, which is mediated by FAMB.
Z36 is a tiny molecule that has been shown to cause cancer cell death by promoting excessive ER-phagy and inducing the expression of FAMB in HeLa cells [ ]. It has been shown that FAMB can prevent the development of colorectal and breast cancer [ , ]. The suppressive effect of FAMB on cancer needs to be further studied and tested in clinical practice.
It has long been known that infections play a major part in the growth of sporadic malignancies caused by genomic instability or DNA damage. These conditions are associated with the generation of toxic metabolites and chronic inflammation mediated by pathogens.
Through interacting and activating oncoproteins of the host, bacterial effectors contribute to cell cycle dysregulation and thus carcinogenesis [ 69 ].
Cell death mediated by xenophagy is favorable to tumor regression. It can also serve as a protector to slow down tumor growth by preventing bacterial infection [ , ]. Since bacteria-associated xenophagy is able to influence the microbiota and then triggers carcinogenesis via stimulating inflammation, antimicrobial agents may have the potential to prevent cancers by regulating xenophagy [ ].
The main factor contributing to stomach cancer carcinogenesis is an infection with Helicobacter pylori H. Cytotoxin A VacA and cytotoxin-associated gene A CagA are the two main bacterial proteins that H. pylori uses to regulate gastric epithelial cells. An acute exposure to VacA prevents H.
pylori infection by inducing xenophagy, while a long-term exposure strongly disrupts xenophagy, promotes infection and eventually causes carcinogenesis by upregulating SQSTM1, and increasing the accumulation of ROS and toxins [ ].
There is a close correlation between the carcinogenesis of gastric cancer and the continuous expression of CagA. Infected cells generally undergo xenophagy triggered by ROS to breakdown CagA [ 68 ]. peptidoglycan deacetylase PgdA is essential for controlling the inflammatory response to H.
pylori infection by reducing NOD1-dependent activation of NF-κB and inhibiting xenophagy, which eventually induces gastric cancer [ ]. Xenophagy is a key mechanism in recognizing H. pylori and inducing H. pylori -associated gastric cancer. The xenophagy in cells is significantly suppressed by the extremely pathogenic H.
pylori strain GC The rs mutation in the autophagy-related like 1 Atg16L1 gene is associated with higher incidence of gastric cancer and H. pylori infection, which implies that defective xenophagy may be involved in the carcinogenesis of gastric cancer [ ].
When Salmonella accumulatively lives in malignant lesions, strong xenophagy is induced by cancer cells in order to eradicate the bacteria through LC3 processing. In hepatocellular carcinoma cells, tumor-targeting Salmonella typhimurium A1-R or the strain VNP of the bacterium causes xenophagy, which wards off infection by cancer cells [ ].
Knockdown of Atg5 or BECN1 in cancer cells infected with bacteria significantly increases bacterial proliferation and slows down cancer cell growth [ ].
Therefore, a combination therapy of Salmonella -targeted xenophagy blockade and anti-infection treatment is a promising anti-cancer strategy.
Lipophagy is an alternative of lipid droplet degradation, which is a key factor for carcinogenesis and metastasis by mediating lipid turnover. Cancer cells typically encourage the synthesis and uptake of fatty acids, which causes the production of lipid droplets [ ].
In times of stress or nutrient deprivation, lipophagy supplies lipid metabolites for the synthesis of macromolecules, which may contribute to cancer cell survival [ ]. For example, lysosomal acid lipase LAL inhibition helps prevent prostate cancer by preventing the creation of free fatty acids and reactive oxygen species ROS that are produced as a result of lipase activity [ ].
Suppressing lipophagy is linked with increased cancer aggressiveness [ , ] and chemotherapy resistance [ ]. LAL deficiency results in hematopoietic abnormalities. Then, immunological evasion and cancer cell metastasis are made possible by massive immature myeloid-derived suppressor cells MSDCs , which act as a mediator in the immune surveillance suppressing [ , ].
Enhancement of lipid metabolism can alleviate the metastasis of lung and liver cancer [ ]. According to a study, lipophagy mediates ER stress by accumulating free fatty acids, which makes cancer cells more susceptible to death [ ].
As a type of lipid metabolism, lipophagy is considered as a promising anti-cancer treatment. Lysosomes contain hydrolytic enzymes like cathepsins that degrade proteins during autophagy.
Macrocytosis that relies on the degradation of extracellular materials via lysosomes is stimulated in nutrient-deficient cancers [ , ]. Lysosomes are involved in drug resistance by blocking anti-cancer agents to their target molecules [ 94 ].
By releasing hydrolases such as cathepsins from the lysosomal lumen into the cytosol, LMP causes necrosis or death in cells. It is an interesting process that may prevent carcinogenic effect of apoptosis as the main cell death mechanism.
LMP induction appears to be a successful method of killing cancer cells, given the critical roles that functional lysosomes play in drug resistance and cancer cell survival. Peroxisomes play a vital role in the metabolism of cancer cells by oxidizing several kinds of chemicals, including fatty and amino acids.
Although the specific role of peroxisomes in cancers has not been highlighted, their increased activities may promote the malignant growth via lipid oxidation [ ].
Acetyl-CoA oxidase 1 ACOX1 and other peroxidase metabolism-related genes can have their expression levels controlled by peroxisome proliferator-activated receptors PPARs [ ]. A poorer prognosis for HER2-positive breast cancer is associated with high levels of ACOX1 [ ].
Alpha-methylacyl-CoA racemase AMACR participate in the α-oxidation of molecules and the preparation for β-oxidation. The overexpression of AMACR is associated with low survival of prostate cancer [ ], colon cancer [ ], gastric cancer [ ], breast cancer [ ], renal and hepatocellular carcinoma [ ], and myxofibrosarcoma [ ].
Autophagy can act as a promoter or inhibitor of cancer, which makes it a promising and challenging therapeutic target [ ]. At present, only chloroquine CQ and its derived hydroxychloroquine HCQ are FDA-approved drugs to inhibit autophagy.
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