bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024–06–23
nine papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. A genetically-encoded fluorescence-based reporter to spatiotemporally investigate mannose-6-phosphate pathway.
  2. Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease.
  3. Structure of the endosomal CORVET tethering complex.
  4. Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.
  5. Underlying Mechanism of Lysosomal Membrane Permeabilization in CNS Injury: A Literature Review.
  6. Farrerol Alleviates Diabetic Cardiomyopathy by Regulating AMPK-Mediated Cardiac Lipid Metabolic Pathways in Type 2 Diabetic Rats.
  7. AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
  8. Extracellular Vesicles in Diabetic Cardiomyopathy-State of the Art and Future Perspectives.
  9. Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.
  1. Mol Biol Cell. 2024 Jun 18. mbcE23090344
    A genetically-encoded fluorescence-based reporter to spatiotemporally investigate mannose-6-phosphate pathway.
    Mallika Bhat, Akshaya Nambiar, Lakshmi Edakkandiyil, Irine Maria Abraham, Ritoprova Sen, Mamta Negi, Ravi Manjithaya.
      Maintenance of a pool of active lysosomes with acidic pH and degradative hydrolases is crucial for cell health. Abnormalities in lysosomal function are closely linked to diseases, such as lysosomal storage disorders (LSDs), neurodegeneration, intracellular infections, and cancer among others. Emerging body of research suggests the malfunction of lysosomal hydrolase trafficking pathway to be a common denominator of several disease pathologies. However, available conventional tools to assess lysosomal hydrolase trafficking are insufficient and fail to provide a comprehensive picture about the trafficking flux and location of lysosomal hydrolases. To address some of the shortcomings, we designed a genetically encoded fluorescent reporter containing a lysosomal hydrolase tandemly tagged with pH sensitive and insensitive fluorescent proteins, which can spatio-temporally trace the trafficking of lysosomal hydrolases. As a proof of principle, we demonstrate that the reporter can detect perturbations in hydrolase trafficking, that are induced by pharmacological manipulations and pathophysiological conditions like intracellular protein aggregates. This reporter can effectively serve as a probe for mapping the mechanistic intricacies of hydrolase trafficking pathway in health and disease and is a utilitarian tool to identify genetic and pharmacological modulators of this pathway, with potential therapeutic implications.
    DOI:  https://doi.org/10.1091/mbc.E23-09-0344
  2. Elife. 2024 Jun 20. pii: e98649. [Epub ahead of print]13
    Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease.
    Yuki Date, Yukiko Sasazawa, Mitsuhiro Kitagawa, Kentaro Gejima, Ayami Suzuki, Hideyuki Saya, Yasuyuki Kida, Masaya Imoto, Eisuke Itakura, Nobutaka Hattori, Shinji Saiki.
      The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including a-synuclein (aSyn) associated with the pathogenesis of Parkinson's disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning. Through high-throughput chemical screening, we identified 6 out of 1,200 clinically approved drugs enabling the lysosomes to accumulate around the MTOC with autophagy flux enhancement. We further demonstrated that these compounds induce the lysosomal clustering through a JIP4-TRPML1-dependent mechanism. Among them, the lysosomal-clustering compound albendazole promoted the autophagy-dependent degradation of Triton-X-insoluble, proteasome inhibitor-induced aggregates. In a cellular PD model, albendazole boosted insoluble aSyn degradation. Our results revealed that lysosomal clustering can facilitate the breakdown of protein aggregates, suggesting that lysosome-clustering compounds may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.
    Keywords:  cell biology
    DOI:  https://doi.org/10.7554/eLife.98649
  3. Nat Commun. 2024 Jun 19. 15(1): 5227
    Structure of the endosomal CORVET tethering complex.
    Dmitry Shvarev, Caroline König, Nicole Susan, Lars Langemeyer, Stefan Walter, Angela Perz, Florian Fröhlich, Christian Ungermann, Arne Moeller.
      Cells depend on their endolysosomal system for nutrient uptake and downregulation of plasma membrane proteins. These processes rely on endosomal maturation, which requires multiple membrane fusion steps. Early endosome fusion is promoted by the Rab5 GTPase and its effector, the hexameric CORVET tethering complex, which is homologous to the lysosomal HOPS. How these related complexes recognize their specific target membranes remains entirely elusive. Here, we solve the structure of CORVET by cryo-electron microscopy and revealed its minimal requirements for membrane tethering. As expected, the core of CORVET and HOPS resembles each other. However, the function-defining subunits show marked structural differences. Notably, we discover that unlike HOPS, CORVET depends not only on Rab5 but also on phosphatidylinositol-3-phosphate (PI3P) and membrane lipid packing defects for tethering, implying that an organelle-specific membrane code enables fusion. Our data suggest that both shape and membrane interactions of CORVET and HOPS are conserved in metazoans, thus providing a paradigm how tethering complexes function.
    DOI:  https://doi.org/10.1038/s41467-024-49137-9
  4. Proc Natl Acad Sci U S A. 2024 Jun 25. 121(26): e2317945121
    Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.
    Maryam Jafari, Adrián Macho-González, Antonio Diaz, Kristen Lindenau, Olaya Santiago-Fernández, Mei Zeng, Ashish C Massey, Rafael de Cabo, Susmita Kaushik, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types. A decrease in lysosomal levels of the lysosome-associated membrane protein type 2A (LAMP2A), the CMA receptor, has been identified as a main reason for declined CMA in aging. Here, we report constitutive activation of CMA with calorie restriction (CR), an intervention that extends healthspan, in old rodent livers and in an in vitro model of CR with cultured fibroblasts. We found that CR-mediated upregulation of CMA is due to improved stability of LAMP2A at the lysosome membrane. We also explore the translational value of our observations using calorie-restriction mimetics (CRMs), pharmacologically active substances that reproduce the biochemical and functional effects of CR. We show that acute treatment of old mice with CRMs also robustly activates CMA in several tissues and that this activation is required for the higher resistance to lipid dietary challenges conferred by treatment with CRMs. We conclude that part of the beneficial effects associated with CR/CRMs could be a consequence of the constitutive activation of CMA mediated by these interventions.
    Keywords:  aging; autophagy; dietary restriction; gerotherapeutics; lysosomes
    DOI:  https://doi.org/10.1073/pnas.2317945121
  5. Mol Neurobiol. 2024 Jun 18.
    Underlying Mechanism of Lysosomal Membrane Permeabilization in CNS Injury: A Literature Review.
    Linyi Xiang, Junsheng Lou, Jiayi Zhao, Yibo Geng, Jiacheng Zhang, Yuzhe Wu, Yinuo Zhao, Zhichao Tao, Yao Li, Jianjun Qi, Jiaoxiang Chen, Liangliang Yang, Kailiang Zhou.
      Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury.
    Keywords:  CNS injury; Cathepsin; Inflammation; Lysosomal membrane permeabilization; Programmed cell death
    DOI:  https://doi.org/10.1007/s12035-024-04290-6
  6. Cell Biochem Biophys. 2024 Jun 15.
    Farrerol Alleviates Diabetic Cardiomyopathy by Regulating AMPK-Mediated Cardiac Lipid Metabolic Pathways in Type 2 Diabetic Rats.
    Jia Tu, Qiaoling Liu, Huirong Sun, Luzhen Gan.
      Diabetic cardiomyopathy (DCM) is a prevalent complication of diabetes mellitus characterized by cardiac dysfunction and myocardial remodeling. Farrerol (FA), an active ingredient in Rhododendron with various pharmacological activities, has an unclear specific role in DCM. Therefore, this study aims to investigate the effects of FA on DCM rats and elucidate its mechanism. The type 2 diabetes mellitus (T2DM) model was induced in adult male Sprague-Dawley rats by administering a high-fat diet for 8 weeks along with STZ injection. Subsequent to successful modeling, FA and the positive drug Dapagliflozin (Dapa) were orally administered via gavage for an additional 8-week period. After administration, the rats' body weight, fasting blood glucose, fasting insulin, and blood lipid profiles were quantified. Cardiac function was assessed through evaluation of cardiac function parameters, histopathological examination and measurement of myocardial enzyme markers were conducted to assess myocardial injury and fibrosis, Oil red O staining was utilized to evaluate myocardial lipid accumulation, wheat germ agglutinin (WGA) staining was used for assessing cardiomyocyte hypertrophy, and Western blot analysis was used to detect the proteins expression level of AMP-activated protein kinase (AMPK) pathway. The rat cardiomyocyte H9c2 were induced with palmitic acid to establish an in vitro cell model of myocardial lipid toxicity. Subsequently, the cells were subjected to treatment with FA and AMPK inhibitor Compound C, followed by assessment of lipid formation and expression levels of proteins related to the AMPK signaling pathway. The findings demonstrated that both FA and Dapa exhibited efficacy in ameliorating diabetic symptoms, cardiac dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, and lipid accumulation in T2DM rats. Additionally, they were found to enhance AMPK phosphorylation and PPARα expression while down-regulating CD36. Similarly, FA was observed to inhibit lipid formation in H9c2 and activate the AMPK signaling pathway. However, the improved effect of FA on lipotoxic cardiomyocytes induced by palmitic acid was partially reversed by Compound C. Therefore, the activation of the AMPK signaling pathway by FA may enhance cardiac lipid metabolism, thereby improving cardiac dysfunction and myocardial fibrosis in DCM rats.
    Keywords:  AMP-activated protein kinase; Diabetic cardiomyopathy; Farrerol; Lipid metabolism
    DOI:  https://doi.org/10.1007/s12013-024-01353-2
  7. Cell Res. 2024 Jun 19.
    AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
    Mengqi Li, Yu Wang, Xiaoyan Wei, Wei-Feng Cai, Jianfeng Wu, Mingxia Zhu, Yongliang Wang, Yan-Hui Liu, Jinye Xiong, Qi Qu, Yan Chen, Xiao Tian, Luming Yao, Renxiang Xie, Xiaomin Li, Siwei Chen, Xi Huang, Cixiong Zhang, Changchuan Xie, Yaying Wu, Zheni Xu, Baoding Zhang, Bin Jiang, Zhi-Chao Wang, Qinxi Li, Gang Li, Shu-Yong Lin, Li Yu, Hai-Long Piao, Xianming Deng, Jiahuai Han, Chen-Song Zhang, Sheng-Cai Lin.
      The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.
    DOI:  https://doi.org/10.1038/s41422-024-00985-6
  8. Int J Mol Sci. 2024 Jun 01. pii: 6117. [Epub ahead of print]25(11):
    Extracellular Vesicles in Diabetic Cardiomyopathy-State of the Art and Future Perspectives.
    Przemysław Zygmunciak, Katarzyna Stróżna, Olga Błażowska, Beata Mrozikiewicz-Rakowska.
      Cardiovascular complications are the most deadly and cost-driving effects of diabetes mellitus (DM). One of them, which is steadily attracting attention among scientists, is diabetes-induced heart failure, also known as diabetic cardiomyopathy (DCM). Despite significant progress in the research concerning the disease, a universally accepted definition is still lacking. The pathophysiology of the processes accelerating heart insufficiency in diabetic patients on molecular and cellular levels also remains elusive. However, the recent interest concerning extracellular vesicles (EVs) has brought promise to further clarifying the pathological events that lead to DCM. In this review, we sum up recent investigations on the involvement of EVs in DCM and show their therapeutic and indicatory potential.
    Keywords:  DCM; diabetes; diabetic cardiomyopathy; exosomes; extracellular vesicles; heart failure; micro-RNA
    DOI:  https://doi.org/10.3390/ijms25116117
  9. J Am Chem Soc. 2024 Jun 20.
    Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.
    Jinyan Luo, Quan Gao, Kui Tan, Shiling Zhang, Weiwei Shi, Lei Luo, Zhiying Li, Ghada E Khedr, Jie Chen, Youwei Xu, Ming Luo, Qi Xing, Jin Geng.
      Targeted protein degradation technology holds great potential in biomedicine, particularly in treating tumors and other protein-related diseases. Research on intracellular protein degradation using molecular glues and PROTAC technology is leading, while research on the degradation of membrane proteins and extracellular proteins through the lysosomal pathway is still in the preclinical stage. The scarcity of useful targets is an immense limitation to technological advancement, making it essential to explore novel, potentially effective approaches for targeted lysosomal degradation. Here, we employed the glucose transporter Glut1 as an innovative lysosome-targeting receptor and devised the Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized potential Glut1 ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization and acquired antibody-glycooligomer conjugates through bioorthogonal reactions as lysosome-targeting protein degradation molecules, utilized in the management of PD-L1 high-expressing triple-negative breast cancer. The glucose transporter Glut1 as a lysosome-targeting receptor exhibits potential for the advancement of a broader array of medications in the future.
    DOI:  https://doi.org/10.1021/jacs.4c02463
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