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Seminars in Cell & Developmental Biology 2024The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental... (Review)
Review
The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.
Topics: Humans; Mitochondrial Dynamics; Autophagy; Mitophagy; Mitochondria; Homeostasis
PubMed: 38430721
DOI: 10.1016/j.semcdb.2024.02.001 -
Molecular Cell May 2024Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases,...
Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases, including Huntington's disease (HD). Huntingtin (Htt), the disease protein of HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but the efficiency of aggrephagy is limited. Here, we used cryo-electron tomography to visualize the interactions of autophagosomes with polyQ aggregates in cultured cells in situ. We found that an amorphous aggregate phase exists next to the radially organized polyQ fibrils. Autophagosomes preferentially engulfed this amorphous material, mediated by interactions between the autophagy receptor p62/SQSTM1 and the non-fibrillar aggregate surface. In contrast, amyloid fibrils excluded p62 and evaded clearance, resulting in trapping of autophagic structures. These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.
Topics: Peptides; Autophagy; Humans; Huntingtin Protein; Autophagosomes; Sequestosome-1 Protein; Amyloid; Huntington Disease; Protein Aggregates; Cryoelectron Microscopy; Animals; Protein Aggregation, Pathological
PubMed: 38759629
DOI: 10.1016/j.molcel.2024.04.018 -
The Journal of Cell Biology Aug 2023In macroautophagy, cellular components are sequestered within autophagosomes and transported to lysosomes/vacuoles for degradation. Although phosphatidylinositol...
In macroautophagy, cellular components are sequestered within autophagosomes and transported to lysosomes/vacuoles for degradation. Although phosphatidylinositol 3-kinase complex I (PI3KCI) plays a pivotal role in the regulation of autophagosome biogenesis, little is known about how this complex localizes to the pre-autophagosomal structure (PAS). In Saccharomyces cerevisiae, PI3KCI is composed of PI3K Vps34 and conserved subunits Vps15, Vps30, Atg14, and Atg38. In this study, we discover that PI3KCI interacts with the vacuolar membrane anchor Vac8, the PAS scaffold Atg1 complex, and the pre-autophagosomal vesicle component Atg9 via the Atg14 C-terminal region, the Atg38 C-terminal region, and the Vps30 BARA domain, respectively. While the Atg14-Vac8 interaction is constitutive, the Atg38-Atg1 complex interaction and the Vps30-Atg9 interaction are enhanced upon macroautophagy induction depending on Atg1 kinase activity. These interactions cooperate to target PI3KCI to the PAS. These findings provide a molecular basis for PAS targeting of PI3KCI during autophagosome biogenesis.
Topics: Autophagosomes; Autophagy; Autophagy-Related Proteins; Membrane Proteins; Phosphatidylinositol 3-Kinases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Vesicular Transport Proteins
PubMed: 37436710
DOI: 10.1083/jcb.202210017 -
IScience Nov 2023-GlcNAcylation is a key post-translational modification, playing a vital role in cell signaling during development, especially in the brain. In this study, we...
-GlcNAcylation is a key post-translational modification, playing a vital role in cell signaling during development, especially in the brain. In this study, we investigated the role of -GlcNAcylation in regulating the homeobox protein OTX2, which contributes to various brain disorders, such as combined pituitary hormone deficiency, retinopathy, and medulloblastoma. Our research demonstrated that, under normal physiological conditions, the proteasome plays a pivotal role in breaking down endogenous OTX2. However, when the levels of OTX2 rise, it forms oligomers and/or aggregates that require macroautophagy for clearance. Intriguingly, we demonstrated that -GlcNAcylation enhances the solubility of OTX2, thereby limiting the formation of these aggregates. Additionally, we unveiled an interaction between OTX2 and the chaperone protein CCT5 at the -GlcNAc sites, suggesting a potential collaborative role in preventing OTX2 aggregation. Finally, our study demonstrated that while OTX2 physiologically promotes cell proliferation, an -GlcNAc-depleted OTX2 is detrimental to cancer cells.
PubMed: 38026167
DOI: 10.1016/j.isci.2023.108184 -
International Journal of Molecular... Nov 2023Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy...
Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, the role of PHB2 in prion diseases remains unclear. In this study, we isolated primary cortical neurons from rats and used the neurotoxic prion peptide PrP as a cell model for prion diseases. We examined the role of PHB2 in PrP-induced mitophagy using Western blotting and immunofluorescence microscopy and assessed the function of PHB2 in PrP-induced neuronal death using the cell viability assay and the TUNEL assay. The results showed that PrP induced mitochondrial morphological abnormalities and mitophagy in primary cortical neurons. PHB2 was found to be indispensable for PrP-induced mitophagy and was involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria in primary neurons. Additionally, PHB2 depletion exacerbated neuronal cell death induced by PrP, whereas the overexpression of PHB2 alleviated PrP neuronal toxicity. Taken together, this study demonstrated that PHB2 is indispensable for PINK1/Parkin-mediated mitophagy in PrP-treated neurons and protects neurons against the neurotoxicity of the prion peptide.
Topics: Animals; Rats; Mitophagy; Neurotoxicity Syndromes; Peptides; Prion Diseases; Prions; Protein Kinases; Ubiquitin-Protein Ligases
PubMed: 37958902
DOI: 10.3390/ijms242115919 -
Journal of Molecular Biology Feb 2024Autophagy mediates the degradation and recycling of cellular material in the lysosomal system. Dysfunctional autophagy is associated with a plethora of diseases... (Review)
Review
Autophagy mediates the degradation and recycling of cellular material in the lysosomal system. Dysfunctional autophagy is associated with a plethora of diseases including uncontrolled infections, cancer and neurodegeneration. In macroautophagy (hereafter autophagy) this material is encapsulated in double membrane vesicles, the autophagosomes, which form upon induction of autophagy. The precursors to autophagosomes, referred to as phagophores, first appear as small flattened membrane cisternae, which gradually enclose the cargo material as they grow. The assembly of phagophores during autophagy initiation has been a major subject of investigation over the past decades. A special focus has been ATG9, the only conserved transmembrane protein among the core machinery. The majority of ATG9 localizes to small Golgi-derived vesicles. Here we review the recent advances and breakthroughs regarding our understanding of how ATG9 and the vesicles it resides in serve to assemble the autophagy machinery and to establish membrane contact sites for autophagosome biogenesis. We also highlight open questions in the field that need to be addressed in the years to come.
PubMed: 38342428
DOI: 10.1016/j.jmb.2024.168489 -
Plant Physiology Sep 2023The selective turnover of macromolecules by autophagy provides a critical homeostatic mechanism for recycling cellular constituents and for removing superfluous and...
The selective turnover of macromolecules by autophagy provides a critical homeostatic mechanism for recycling cellular constituents and for removing superfluous and damaged organelles, membranes, and proteins. To better understand how autophagy impacts seed maturation and nutrient storage, we studied maize (Zea mays) endosperm in its early and middle developmental stages via an integrated multiomic approach using mutants impacting the core macroautophagy factor AUTOPHAGY (ATG)-12 required for autophagosome assembly. Surprisingly, the mutant endosperm in these developmental windows accumulated normal amounts of starch and Zein storage proteins. However, the tissue acquired a substantially altered metabolome, especially for compounds related to oxidative stress and sulfur metabolism, including increases in cystine, dehydroascorbate, cys-glutathione disulfide, glucarate, and galactarate, and decreases in peroxide and the antioxidant glutathione. While changes in the associated transcriptome were mild, the proteome was strongly altered in the atg12 endosperm, especially for increased levels of mitochondrial proteins without a concomitant increase in mRNA abundances. Although fewer mitochondria were seen cytologically, a heightened number appeared dysfunctional based on the accumulation of dilated cristae, consistent with attenuated mitophagy. Collectively, our results confirm that macroautophagy plays a minor role in the accumulation of starch and storage proteins during maize endosperm development but likely helps protect against oxidative stress and clears unneeded/dysfunctional mitochondria during tissue maturation.
Topics: Endosperm; Zea mays; Starch; Autophagy; Mitochondria; Oxidative Stress
PubMed: 37335933
DOI: 10.1093/plphys/kiad340 -
Pharmacological Research Aug 2023Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The...
Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The genomic profile alterations and dysregulated biological mechanisms commonly occur in PC. Macroautophagy/autophagy is a cell death process that is maintained at a basal level in physiological conditions, whereas its level often changes during tumorigenesis. The function of autophagy in human cancers is dual and can be oncogenic and onco-suppressor. Autophagy is a potent controller of tumorigenesis in PC. The supportive autophagy in PC escalates the growth rate of PC cells and its suppression can mediate cell death. Autophagy also determines the metastasis of PC cells, and it can control the EMT in affecting migration. Moreover, starvation and hypoxia can stimulate glycolysis, and glycolysis induction can be mediated by autophagy in enhancing tumorigenesis in PC. Furthermore, protective autophagy stimulates drug resistance and gemcitabine resistance in PC cells, and its inhibition can enhance radiosensitivity. Autophagy can degrade MHC-I to mediate immune evasion and also regulates polarization of macrophages in the tumor microenvironment. Modulation of autophagy activity is provided by silibinin, ursolic acid, chrysin and huaier in the treatment of PC. Non-coding RNAs are also controllers of autophagy in PC and its inhibition can improve therapy response in patients. Moreover, mitophagy shows dysregulation in PC, which can enhance the proliferation of PC cells. Therefore, a bioinformatics analysis demonstrates the dysregulation of autophagy-related proteins and genes in PC as biomarkers.
Topics: Humans; Cell Line, Tumor; Pancreatic Neoplasms; Autophagy; Carcinogenesis; Tumor Microenvironment
PubMed: 37336429
DOI: 10.1016/j.phrs.2023.106822 -
Autophagy Oct 2023Mitochondrial DNA (mtDNA) is prone to the accumulation of mutations. To prevent harmful mtDNA mutations from being passed on to the next generation, the female germline,...
Mitochondrial DNA (mtDNA) is prone to the accumulation of mutations. To prevent harmful mtDNA mutations from being passed on to the next generation, the female germline, through which mtDNA is exclusively inherited, has evolved extensive mtDNA quality control. To dissect the molecular underpinnings of this process, we recently performed a large RNAi screen in Drosophila and uncovered a programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We found that PGM begins as germ cells enter meiosis, induced, at least in part, by the inhibition of the mTor (mechanistic Target of rapamycin) complex 1 (mTorC1). Interestingly, PGM requires the general macroautophagy/autophagy machinery and the mitophagy adaptor BNIP3, but not the canonical mitophagy genes Pink1 and park (parkin), even though they are critical for germline mtDNA quality control. We also identified the RNA-binding protein Atx2 as a major regulator of PGM. This work is the first to identify and implicate a programmed mitophagy event in germline mtDNA quality control, and it highlights the utility of the Drosophila ovary for studying developmentally regulated mitophagy and autophagy .
Topics: Animals; Female; Mitophagy; Autophagy; DNA, Mitochondrial; Ubiquitin-Protein Ligases; Mechanistic Target of Rapamycin Complex 1; Drosophila; Germ Cells
PubMed: 36803283
DOI: 10.1080/15548627.2023.2182595 -
Biology Sep 2023Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of... (Review)
Review
Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of developing different cardiometabolic diseases like diabetes. Cellular senescence and autophagy, both hallmarks of aging and stress-coping mechanisms, have gained increased attention for their role in the pathophysiology of diabetes. Studies show that impairing senescence dampens and even prevents diabetes while the role of autophagy is more contradictory, implying a context- and disease-stage-dependent effect. Reports show conflicting data about the effect of autophagy on senescence while the knowledge about this interaction in beta cells remains scarce. Elucidating this interaction between autophagy and senescence in pancreatic beta cells will lead to an identification of their respective roles and the extent of the effect each mechanism has on beta cells and open new horizons for developing novel therapeutic agents. To help illuminate this relationship we will review the latest findings of cellular senescence and autophagy with a special emphasis on pancreatic beta cells and diabetes.
PubMed: 37759604
DOI: 10.3390/biology12091205