bims-tofagi Biomed News
on Mitophagy
Issue of 2023‒09‒24
fourteen papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea
  1. Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
  2. Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.
  3. Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.
  4. Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
  5. Contribution and therapeutic value of mitophagy in cerebral ischemia-reperfusion injury after cardiac arrest.
  6. Evolutionarily acquired response of selective autophagy receptors provides resilience against oxidative stress.
  7. Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.
  8. Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
  9. Focused low-intensity pulsed ultrasound alleviates osteoarthritis via restoring impaired FUNDC1-mediated mitophagy.
  10. Blockade of hepatocyte PCSK9 ameliorates hepatic ischemia- reperfusion injury by promoting pink1-parkin-mediated mitophagy.
  11. Urolithin A Prevents Sleep-deprivation-induced Neuroinflammation and Mitochondrial Dysfunction in Young and Aged Mice.
  12. Artesunate Sensitizes Human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy.
  13. The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
  14. A mechanism that ensures non-selective cytoplasm degradation by autophagy.
  1. Sci Adv. 2023 Sep 22. 9(38): eadh8228
    Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
    Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.
      Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.
    DOI:  https://doi.org/10.1126/sciadv.adh8228
  2. Neuron. 2023 Sep 13. pii: S0896-6273(23)00629-3. [Epub ahead of print]
    Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.
    Pingping Song, Wesley Peng, Veronique Sauve, Rayan Fakih, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette C Wong, Niccolò E Mencacci, Jeffrey N Savas, D James Surmeier, Kalle Gehring, Dimitri Krainc.
      Parkin-mediated mitophagy has been studied extensively, but whether mutations in parkin contribute to Parkinson's disease pathogenesis through alternative mechanisms remains unexplored. Using patient-derived dopaminergic neurons, we found that phosphorylation of parkin by Ca2+/calmodulin-dependent protein kinase 2 (CaMK2) at Ser9 leads to activation of parkin in a neuronal-activity-dependent manner. Activated parkin ubiquitinates synaptojanin-1, facilitating its interaction with endophilin A1 and synaptic vesicle recycling. Neurons from PD patients with mutant parkin displayed defective recycling of synaptic vesicles, leading to accumulation of toxic oxidized dopamine that was attenuated by boosting endophilin A1 expression. Notably, combined heterozygous parkin and homozygous PTEN-induced kinase 1 (PINK1) mutations led to earlier disease onset compared with homozygous mutant PINK1 alone, further underscoring a PINK1-independent role for parkin in contributing to disease. Thus, this study identifies a pathway for selective activation of parkin at human dopaminergic synapses and highlights the importance of this mechanism in the pathogenesis of Parkinson's disease.
    Keywords:  CaMK2-mediated activation of parkin; PINK1-independent; Parkinson’s disease; human dopaminergic neurons; synaptic dysfunction; toxic oxidized dopamine
    DOI:  https://doi.org/10.1016/j.neuron.2023.08.018
  3. Front Mol Neurosci. 2023 ;16 1225227
    Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.
    Sholto de Wet, Rensu Theart, Ben Loos.
      Neurodegenerative diseases are often characterized by hydrophobic inclusion bodies, and it may be the case that the aggregate-prone proteins that comprise these inclusion bodies are in fact the cause of neurotoxicity. Indeed, the appearance of protein aggregates leads to a proteostatic imbalance that causes various interruptions in physiological cellular processes, including lysosomal and mitochondrial dysfunction, as well as break down in calcium homeostasis. Oftentimes the approach to counteract proteotoxicity is taken to merely upregulate autophagy, measured by an increase in autophagosomes, without a deeper assessment of contributors toward effective turnover through autophagy. There are various ways in which autophagy is regulated ranging from the mammalian target of rapamycin (mTOR) to acetylation status of proteins. Healthy mitochondria and the intracellular energetic charge they preserve are key for the acidification status of lysosomes and thus ensuring effective clearance of components through the autophagy pathway. Both mitochondria and lysosomes have been shown to bear functional protein complexes that aid in the regulation of autophagy. Indeed, it may be the case that minimizing the proteins associated with the respective neurodegenerative pathology may be of greater importance than addressing molecularly their resulting inclusion bodies. It is in this context that this review will dissect the autophagy signaling pathway, its control and the manner in which it is molecularly and functionally connected with the mitochondrial and lysosomal system, as well as provide a summary of the role of autophagy dysfunction in driving neurodegenerative disease as a means to better position the potential of rapamycin-mediated bioactivities to control autophagy favorably.
    Keywords:  autophagy; lysosomes; mitochondrial function; mitophagy; neurodegenerative diseases; proteostasis
    DOI:  https://doi.org/10.3389/fnmol.2023.1225227
  4. Neurotoxicology. 2023 Sep 16. pii: S0161-813X(23)00124-9. [Epub ahead of print]99 50-58
    Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
    Wenqiong Wang, Rui Chang, Yan Wang, Liyan Hou, Qingshan Wang.
      We recently revealed a pivotal role of NLRP3 inflammasome in the neurotoxicity induced by n-hexane, owing to its activation and release of pro-inflammatory cytokines. However, the mechanisms of how the activation of NLRP3 inflammasome was triggered by 2,5-hexanedione (HD), the toxic product of n-hexane metabolism, remain to be explored. Here, we investigated whether mitochondrial reactive oxygen species (mtROS) was involved in HD-elicited NLRP3 inflammasome activation in microglia. We demonstrated that exposure to HD at 4 and 8 mM elevated production of mtROS in BV2 microglia. Scavenging mtROS by Mito-TEMPO, an mtROS scavenger, dramatically reduced HD-induced NLRP3 expression, caspase-1 activation and interleukin-1β production, pointing a crucial role of mtROS in NLRP3 inflammasome activation. Mechanistic study revealed that HD intoxication promoted activation of mitophagy. HD induced expression of Beclin-1, LC3II, and two mitophagy-related proteins, i.e., Pink1 and Parkin and simultaneously, reduced p62 expression in both whole cell and isolated mitochondria of microglia. Furthermore, inhibition of mitophagy by 3-methyladenine (3-MA) greatly reduced production of mtROS, expression of mitochondrial fission-related proteins, dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) and activation of NLRP3 inflammasome in HD-intoxicated microglia. Blocking mitochondrial fission by Mdivi-1 also prevented HD-induced mtROS production and NLRP3 inflammasome activation in microglia. In conclusion, our data indicated that HD triggered activation of NLRP3 inflammasome through mitophagy-dependent mtROS production, offering an important insight for the immunopathogenesis of environmental toxins-induced neuroinflammation and neurotoxicity.
    Keywords:  Mitochondrial ROS; Mitochondrial fission; Mitophagy; N-Hexane; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.neuro.2023.09.008
  5. Biomed Pharmacother. 2023 Sep 14. pii: S0753-3322(23)01290-8. [Epub ahead of print]167 115492
    Contribution and therapeutic value of mitophagy in cerebral ischemia-reperfusion injury after cardiac arrest.
    Zheng Li, Jihong Xing.
      Cardiopulmonary resuscitation and related life support technologies have improved substantially in recent years; however, mortality and disability rates from cardiac arrest (CA) remain high and are closely associated with the high incidence of cerebral ischemia-reperfusion injury (CIRI), which is explained by a "double-hit" model (i.e., resulting from both ischemia and reperfusion). Mitochondria are important power plants in the cell and participate in various biochemical processes, such as cell differentiation and signaling in eukaryotes. Various mitochondrial processes, including energy metabolism, calcium homeostasis, free radical production, and apoptosis, are involved in several important stages of the progression and development of CIRI. Mitophagy is a key mechanism of the endogenous removal of damaged mitochondria to maintain organelle function and is a critical target for CIRI treatment after CA. Mitophagy also plays an essential role in attenuating ischemia-reperfusion in other organs, particularly during post-cardiac arrest myocardial dysfunction. Regulation of mitophagy may influence necroptosis (a programmed cell death pathway), which is the main endpoint of organ ischemia-reperfusion injury. In this review, we summarize the main signaling pathways related to mitophagy and their associated regulatory proteins. New therapeutic methods and drugs targeting mitophagy in ischemia-reperfusion animal models are also discussed. In-depth studies of the mechanisms underlying the regulation of mitophagy will enhance our understanding of the damage and repair processes in CIRI after CA, thereby contributing to the development of new therapeutic strategies.
    Keywords:  Cardiac arrest; Cerebral ischemia and reperfusion; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.biopha.2023.115492
  6. Bioessays. 2023 Sep 19. e2300168
    Evolutionarily acquired response of selective autophagy receptors provides resilience against oxidative stress.
    Fazilet Bekbulat.
      
    Keywords:  aggrephagy; aging; autophagy; mitophagy; neurodegeneration; oxidative stress; selective autophagy receptors
    DOI:  https://doi.org/10.1002/bies.202300168
  7. Sci Immunol. 2023 Sep 29. 8(87): eadf7579
    Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.
    Fabien Franco, Alessio Bevilacqua, Ruey-Mei Wu, Kung-Chi Kao, Chun-Pu Lin, Lorène Rousseau, Fu-Ti Peng, Yu-Ming Chuang, Jhan-Jie Peng, Jaeoh Park, Yingxi Xu, Antonino Cassotta, Yi-Ru Yu, Daniel E Speiser, Federica Sallusto, Ping-Chih Ho.
      Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.
    DOI:  https://doi.org/10.1126/sciimmunol.adf7579
  8. PLoS Biol. 2023 Sep 18. 21(9): e3002310
    Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
    Xenia Chelius, Veronika Bartosch, Nathalie Rausch, Magdalena Haubner, Jana Schramm, Ralf J Braun, Till Klecker, Benedikt Westermann.
      Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.
    DOI:  https://doi.org/10.1371/journal.pbio.3002310
  9. iScience. 2023 Oct 20. 26(10): 107772
    Focused low-intensity pulsed ultrasound alleviates osteoarthritis via restoring impaired FUNDC1-mediated mitophagy.
    Haixia Ye, Dongqian Li, Xia Wei, Lehua Yu, Lang Jia.
      Mitophagy is critical for maintaining proper cellular functions, and it contributes to the onset and progression of osteoarthritis (OA). A recent study showed that focused low-intensity pulsed ultrasound (FLIPUS) could activate mitophagy, but the molecular mechanism remains unclear. This study aimed to elucidate the chondroprotective effects of FLIPUS in OA and the regulatory effects on FUN14-domain containing 1 (FUNDC1-mediated mitophagy. In vitro, FLIPUS improved inflammatory response, anabolism, and catabolism in interleukin (IL)-1β-induced OA chondrocytes. The chondroprotective effects of FLIPUS were attributed to promoting the expression of phosphoglycerate mutase 5 (PGAM5) and the dephosphorylation of FUNDC1 at serine 13 (Ser13), as well as promoting the mitophagy process. In vivo, FLIPUS reduced the cartilage degeneration and apoptosis and reversed the change of anabolic- and catabolic-related proteins in destabilized medial meniscus (DMM)-induced mouse model. Thus, the study indicates that FLIPUS exhibits a chondroprotective effect via activating impaired FUNDC1-mediated mitophagy.
    Keywords:  Disease; Immunology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107772
  10. Cell Mol Gastroenterol Hepatol. 2023 Sep 15. pii: S2352-345X(23)00166-2. [Epub ahead of print]
    Blockade of hepatocyte PCSK9 ameliorates hepatic ischemia- reperfusion injury by promoting pink1-parkin-mediated mitophagy.
    Yu Zhang, Ziyi Wang, Chenyang Jia, Wenjie Yu, Xiangdong Li, Nan Xia, Huiling Nie, Pascalia Wikana Likalamu, Minhao Chen, Yong Ni, Sheng Han, Liyong Pu.
      BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI) is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury.METHODS: We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion (IR) models and AML12 cells subjected to hypoxia/reoxygenation (H/R). Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response.
    RESULTS: Our findings reveal that PCSK9 is upregulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy.
    CONCLUSIONS: Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) by promoting pink1-parkin-mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.
    Keywords:  PCSK9; hepatic ischemia-reperfusion; mitophagy; pink1; sting
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.09.004
  11. Mol Neurobiol. 2023 Sep 19.
    Urolithin A Prevents Sleep-deprivation-induced Neuroinflammation and Mitochondrial Dysfunction in Young and Aged Mice.
    Afzal Misrani, Sidra Tabassum, Zai-Yong Zhang, Shao-Hua Tan, Cheng Long.
      Sleep deprivation (SD) has reached epidemic proportions worldwide and negatively affects people of all ages. Cognitive impairment induced by SD involves neuroinflammation and mitochondrial dysfunction, but the underlying mechanisms are largely unknown. Urolithin A (UA) is a natural compound that can reduce neuroinflammation and improve mitochondrial health, but its therapeutic effects in a SD model have not yet been studied. Young (3-months old) and aged (12-months old) mice were sleep deprived for 24 h, and UA (2.5 mg/kg or 10 mg/kg) was injected intraperitoneally for 7 consecutive days before the SD period. Immunofluorescent staining, western blotting, and RT-PCR were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. Transmission electron microscope and Golgi-Cox staining were used to evaluate mitochondrial and neuronal morphology, respectively. Finally, contextual fear conditioning and the Morris water maze test were conducted to assess hippocampal learning and memory. In the hippocampus of young (3 months-old) and aged (12 months-old) mice subjected to 24 h SD, pretreatment with UA prevented the activation of microglia and astrocytes, NF-κB-NLRP3 signaling and IL-1β, IL6, TNF-α cytokine production, thus ameliorating neuroinflammation. Furthermore, UA also attenuated SD-induced mitochondrial dysfunction, normalized autophagy and mitophagy and protected hippocampal neuronal morphology. Finally, UA prevented SD-induced hippocampal memory impairment. Cumulatively, the results show that UA imparts cognitive protection by reducing neuroinflammation and enhancing mitochondrial function in SD mice. This suggests that UA shows promise as a therapeutic for the treatment of SD-induced neurological disorders.
    Keywords:  Hippocampus; Memory impairment; Mitochondrial dysfunction; Neuroinflammation; Sleep deprivation; Urolithin A
    DOI:  https://doi.org/10.1007/s12035-023-03651-x
  12. Autophagy. 2023 Sep 21.
    Artesunate Sensitizes Human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy.
    Zhaochen Ma, Wenjia Chen, Yudong Liu, Lingxiang Yu, Xia Mao, Xiaodong Guo, Funeng Jiang, Qiuyan Guo, Na Lin, Yanqiong Zhang.
      Sorafenib is the most widely used first-line drug for the treatment of the advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance often limits its therapeutic efficacy. To evaluate the efficacy of artesunate against sorafenib-resistant HCC and to investigate its underlying pharmacological mechanisms, a "sorafenib resistance related gene-ART candidate target" interaction network was constructed, and a signaling axis consisting with artesunate candidate target AFAP1L2 and sorafenib target SRC, and the downstream FUNDC1-dependent mitophagy was identified as a major contributor to the sorafenib resistance and a potential way of artesunate to mitigate resistance. Notably, our clinical data demonstrated that AFAP1L2 expression in HCC tissues was markedly higher than that in adjacent non-cancerous liver tissues (P < 0.05), and high AFAP1L2 expression was also significantly associated with an unfavorable overall survival of HCC patients (P < 0.05). Experimentally, AFAP1L2 was overexpressed in sorafenib resistant cells, leading to the activation of downstream SRC-FUNDC1 signaling axis, further blocking the FUNDC1 recruitment of LC3B to mitochondria and inhibiting the activation of mitophagy, based on both in vitro and in vivo systems. Moreover, artesunate significantly enhanced the inhibitory effects of sorafenib on resistant cells and tumors by inducing excessive mitophagy. Mechanically, artesunate reduced the expression of AFAP1L2 protein, suppressed the phosphorylation levels of SRC and FUNDC1 proteins, promoted the FUNDC1 recruitment of massive LC3B to mitochondria, and further overactivated the mitophagy and subsequent cell apoptosis of sorafenib resistant cells. In conclusion, artesunate may be a promising strategy to mitigate sorafenib resistance in HCC via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy.
    Keywords:  AFAP1L2; artesunate; hepatocellular carcinoma; mitophagy; sorafenib resistance
    DOI:  https://doi.org/10.1080/15548627.2023.2261758
  13. J Immunol. 2023 Sep 22. pii: ji2300406. [Epub ahead of print]
    The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
    Dennis Clement, Edina K Szabo, Silje Zandstra Krokeide, Merete Thune Wiiger, Marianna Vincenti, Daniel Palacios, Young-Tae Chang, Christian Grimm, Sandip Patel, Harald Stenmark, Andreas Brech, Rakesh Kumar Majhi, Karl-Johan Malmberg.
      Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1-/- NK92 (NK92ML1-/-) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1-/- cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1.
    DOI:  https://doi.org/10.4049/jimmunol.2300406
  14. Nat Commun. 2023 09 19. 14(1): 5815
    A mechanism that ensures non-selective cytoplasm degradation by autophagy.
    Tetsuya Kotani, Yuji Sakai, Hiromi Kirisako, Chika Kakuta, Soichiro Kakuta, Yoshinori Ohsumi, Hitoshi Nakatogawa.
      In autophagy, a membrane cisterna called the isolation membrane expands, bends, becomes spherical, and closes to sequester cytoplasmic constituents into the resulting double-membrane vesicle autophagosome for lysosomal/vacuolar degradation. Here, we discover a mechanism that allows the isolation membrane to expand with a large opening to ensure non-selective cytoplasm sequestration within the autophagosome. A sorting nexin complex that localizes to the opening edge of the isolation membrane plays a critical role in this process. Without the complex, the isolation membrane expands with a small opening that prevents the entry of particles larger than about 25 nm, including ribosomes and proteasomes, although autophagosomes of nearly normal size eventually form. This study sheds light on membrane morphogenesis during autophagosome formation and selectivity in autophagic degradation.
    DOI:  https://doi.org/10.1038/s41467-023-41525-x
This page is being maintained by Thomas Krichel. It was last updated on 2023‒09‒29 at 10:31.