bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024–10–20
nine papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. A TBK1-independent primordial function of STING in lysosomal biogenesis.
  2. Should it stay or should it go: gap junction protein GJA1/Cx43 conveys damaged lysosomes to the cell periphery to potentiate exocytosis.
  3. Clustering lysosomes around the MTOC: a promising strategy for SNCA/alpha-synuclein breakdown leading to parkinson disease treatment.
  4. Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes.
  5. Transcription factor EB, a promising therapeutic target in cardiovascular disease.
  6. Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
  7. Fueling metabolic adaptation: lysosomal AMPK ignites glutaminolysis.
  8. PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
  9. Editorial: The complex phenotype of diabetic cardiomyopathy: clinical indicators and novel treatment targets.
  1. Mol Cell. 2024 Oct 17. pii: S1097-2765(24)00703-2. [Epub ahead of print]84(20): 3979-3996.e9
    A TBK1-independent primordial function of STING in lysosomal biogenesis.
    Bo Lv, William A Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan.
      Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.
    Keywords:  STING; STING channel; TBK1; TFE3; TFEB; autophagy; cGAS; chronic STING signaling; lysosome
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.026
  2. Autophagy. 2024 Oct 12.
    Should it stay or should it go: gap junction protein GJA1/Cx43 conveys damaged lysosomes to the cell periphery to potentiate exocytosis.
    Neuza Domingues, Teresa Ribeiro-Rodrigues, Henrique Girão.
      GJA1/Cx43 (gap junction protein alpha 1) has long been associated with gap junctions-mediated communication between adjacent cells. However, recent data have defied this concept, with studies implicating GJA1 in other biological processes, such as macroautophagy/autophagy regulation, mitochondrial activity and extracellular vesicles biology. In our recent study we unveiled an additional role played by GJA1 in lysosomal trafficking. We demonstrate that GJA1 promotes the exocytosis of damaged lysosomes, through a mechanism that relies on ACTR2/ARP2-ACTR3/ARP3-dependent actin remodeling. Our findings ascribe to GJA1 an important role during pathogen infection and lysosomal storage disorders, favoring the release of dysfunctional lysosomes.
    Keywords:  Actin; Arp2; gap junction protein alpha 1/Connexin43; lysophagy; lysosomal damage; lysosomal exocytosis
    DOI:  https://doi.org/10.1080/15548627.2024.2408711
  3. Autophagy. 2024 Oct 14. 1-2
    Clustering lysosomes around the MTOC: a promising strategy for SNCA/alpha-synuclein breakdown leading to parkinson disease treatment.
    Yukiko Sasazawa, Yuki Date, Nobutaka Hattori, Shinji Saiki.
      Macroautophagy/autophagy maintains cellular homeostasis by degrading cytoplasmic components and its disruption is linked to Parkinson disease (PD), which is characterized by dopamine depletion and the accumulation of SNCA/α-synuclein aggregates in neurons. Therefore, activation of autophagy is considered a therapeutic strategy for PD; however, autophagy inducers have not yet been developed as therapeutic drugs because they are involved in a wide range of signaling pathways. Here, we focused on the lysosomal clustering around the microtubule-organizing center (MTOC) that can regulate the process of autophagosome-lysosome fusion, the final step of autophagy, and examined how lysosomal clustering affects protein degradation through autophagy. Our study identified six compounds from a high-content screen of 1,200 clinically approved drugs that induce both lysosomal clustering and autophagy. Notably, albendazole reduced SNCA aggregates in a PD model by lysosomal clustering and autophagy. These findings suggest that targeting lysosomal clustering could offer new therapeutic insights for PD.
    Keywords:  Alpha-synuclein; Parkinson disease; autophagy; lysosomal clustering; lysosomal trafficking
    DOI:  https://doi.org/10.1080/15548627.2024.2413295
  4. J Vis Exp. 2024 Sep 27.
    Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes.
    Minkyo Jung, Ji Young Mun.
      Cellular organelles, such as mitochondria and lysosomes, display dynamic structures. Despite the higher resolution of transmission electron microscopy for structural analysis, light microscopy is essential for the visualization of dynamic organelles by target-specific labeling. The following protocol describes a method that combines dual-color correlative light and electron microscopy (CLEM) to observe the interactions between mitochondria and lysosomes. In this study, mitochondria were labeled with mEosEM (Mito-mEosEM) and lysosomes with TMEM192-V5-APEX2. The results obtained from CLEM images enable us to observe the changes in the interactions between mitochondria and lysosomes under external stress conditions. Treatment with bafilomycin (BFA), which inhibits lysosomal function, resulted in an increase in contact between mitochondria and lysosomes, leading to the formation of fragmented mitochondria trapped inside lysosomes. Conversely, treatment with U18666A, which inhibits cholesterol export from lysosomes, caused lysosomes to be surrounded by mitochondria, indicating a distinct form of interaction. This study presents an effective method for observing the interactions between mitochondria and lysosomes in fixed cells. Furthermore, CLEM imaging with dual-color probes offers a powerful tool for future investigations of organelle dynamics and their implications for cell function and pathology.
    DOI:  https://doi.org/10.3791/67020
  5. PeerJ. 2024 ;12 e18209
    Transcription factor EB, a promising therapeutic target in cardiovascular disease.
    Xin Yan, Li Yang, Xiaolei Fu, Xin Luo, Chengming Wang, Qiu Ping Xie, Fan OuYang.
      Cardiovascular disease (CVD) remains the major cause of morbidity and mortality around the world. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis and autophagy. Emerging studies revealed that TFEB also mediates cellular adaptation responses to various stimuli, such as mitochondrial dysfunction, pathogen infection and metabolic toxin. Based on its significant capability to modulate the autophagy-lysosome process (ALP), TFEB plays a critical role in the development of CVD. In this review, we briefly summarize that TFEB regulates cardiac dysfunction mainly through ameliorating lysosomal and mitochondrial dysfunction and reducing inflammation.
    Keywords:  Autophagic flux; Cardiovascular disease; Lysosome; TFEB
    DOI:  https://doi.org/10.7717/peerj.18209
  6. EMBO J. 2024 Oct 17.
    Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
    Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima.
      During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.
    Keywords:  Autophagy; Liquid–Liquid Phase Separation; Mitophagy; Optineurin; Wetting
    DOI:  https://doi.org/10.1038/s44318-024-00272-5
  7. Cell Res. 2024 Oct 14.
    Fueling metabolic adaptation: lysosomal AMPK ignites glutaminolysis.
    Benoit Viollet, Bruno Guigas.
      
    DOI:  https://doi.org/10.1038/s41422-024-01040-0
  8. Cell. 2024 Oct 15. pii: S0092-8674(24)01094-8. [Epub ahead of print]
    PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
    Shubham Singh, Ulrich E Dransfeld, Yohannes A Ambaw, Joshua Lopez-Scarim, Robert V Farese, Tobias C Walther.
      Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer's disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.
    Keywords:  Alzheimer’s disease; dementia; gangliosides; lipid metabolism; lysosome; neurodegeneration; phospholipid
    DOI:  https://doi.org/10.1016/j.cell.2024.09.036
  9. Front Endocrinol (Lausanne). 2024 ;15 1497352
    Editorial: The complex phenotype of diabetic cardiomyopathy: clinical indicators and novel treatment targets.
    Priyanka Choudhury, Ramoji Kosuru, Yin Cai.
      
    Keywords:  cell death; diabetic cardiomyopathy; inflammation; oxidative stress; signaling pathway
    DOI:  https://doi.org/10.3389/fendo.2024.1497352
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