bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024–07–28
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Autophagy and lysosomal dysfunction in diabetes and its complications.
  2. Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.
  3. Cadmium targeting transcription factor EB to inhibit autophagy-lysosome function contributes to acute kidney injury.
  4. Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.
  5. E3 Ubiquitin Ligase RNF13 Suppresses TLR Lysosomal Degradation by Promoting LAMP-1 Proteasomal Degradation.
  6. Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.
  1. Trends Endocrinol Metab. 2024 Jul 24. pii: S1043-2760(24)00170-X. [Epub ahead of print]
    Autophagy and lysosomal dysfunction in diabetes and its complications.
    Catherine Arden, Seo H Park, Xaviera Riani Yasasilka, Eun Y Lee, Myung-Shik Lee.
      Autophagy is critical for energy homeostasis and the function of organelles such as endoplasmic reticulum (ER) and mitochondria. Dysregulated autophagy due to aging, environmental factors, or genetic predisposition can be an underlying cause of not only diabetes through β-cell dysfunction and metabolic inflammation, but also diabetic complications such as diabetic kidney diseases (DKDs). Dysfunction of lysosomes, effector organelles of autophagic degradation, due to metabolic stress or nutrients/metabolites accumulating in metabolic diseases is also emerging as a cause or aggravating element in diabetes and its complications. Here, we discuss the etiological role of dysregulated autophagy and lysosomal dysfunction in diabetes and a potential role of autophagy or lysosomal modulation as a new avenue for treatment of diabetes and its complications.
    Keywords:  autophagy; complications; diabetes; kidney diseases; lysosome
    DOI:  https://doi.org/10.1016/j.tem.2024.06.010
  2. EMBO J. 2024 Jul 23.
    Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.
    Neuza Domingues, Steve Catarino, Beatriz Cristóvão, Lisa Rodrigues, Filomena A Carvalho, Maria João Sarmento, Mónica Zuzarte, Jani Almeida, Teresa Ribeiro-Rodrigues, Ânia Correia-Rodrigues, Fábio Fernandes, Paulo Rodrigues-Santos, Trond Aasen, Nuno C Santos, Viktor I Korolchuk, Teresa Gonçalves, Ira Milosevic, Nuno Raimundo, Henrique Girão.
      A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.
    Keywords:  Actin-remodelling; Arp2; Connexin43; Exocytosis; Lysosomal Damage
    DOI:  https://doi.org/10.1038/s44318-024-00177-3
  3. J Adv Res. 2024 Jul 19. pii: S2090-1232(24)00297-2. [Epub ahead of print]
    Cadmium targeting transcription factor EB to inhibit autophagy-lysosome function contributes to acute kidney injury.
    Peng-Fei Dong, Tian-Bin Liu, Kai Chen, Dan Li, Yue Li, Cai-Yu Lian, Zhen-Yong Wang, Lin Wang.
       INTRODUCTION: Environmental and occupational exposure to cadmium (Cd) has been shown to cause acute kidney injury (AKI). Previous studies have demonstrated that autophagy inhibition and lysosomal dysfunction are important mechanisms of Cd-induced AKI.
    OBJECTIVES: Transcription factor EB (TFEB) is a critical transcription regulator that modulates autophagy-lysosome function, but its role in Cd-induced AKI is yet to be elucidated. Thus, in vivo and in vitro studies were conducted to clarify this issue.
    METHODS AND RESULTS: Data firstly showed that reduced TFEB expression and nuclear translocation were evident in Cd-induced AKI models, accompanied by autophagy-lysosome dysfunction. Pharmacological and genetic activation of TFEB improved Cd-induced AKI via alleviating autophagy inhibition and lysosomal dysfunction, whereas Tfeb knockdown further aggravated this phenomenon, suggesting the key role of TFEB in Cd-induced AKI by regulating autophagy. Mechanistically, Cd activated mechanistic target of rapamycin complex 1 (mTORC1) to enhance TFEB phosphorylation and thereby inhibiting TFEB nuclear translocation. Cd also activated chromosome region maintenance 1 (CRM1) to promote TFEB nuclear export. Meanwhile, Cd activated general control non-repressed protein 5 (GCN5) to enhance nuclear TFEB acetylation, resulting in the decreased TFEB transcriptional activity. Moreover, inhibition of CRM1 or GCN5 alleviated Cd-induced AKI by enhancing TFEB activity, respectively.
    CONCLUSION: In summary, these findings reveal that TFEB phosphorylation, nuclear export and acetylation independently suppress TFEB activity to cause Cd-induced AKI via regulating autophagy-lysosome function, suggesting that TFEB activation might be a promising treatment strategy for Cd-induced AKI.
    Keywords:  Acute kidney injury; Autophagy; Cadmium; Lysosome; transcription factor EB
    DOI:  https://doi.org/10.1016/j.jare.2024.07.013
  4. Nat Commun. 2024 Jul 26. 15(1): 6311
    Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.
    Lifeng Chen, Jingjing Zhang, Weibin Xu, Jiayi Chen, Yujun Tang, Si Xiong, Yaolan Li, Hong Zhang, Manmei Li, Zhong Liu.
      Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2-LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein-dynactin, PLEKHM1, or HOPS VPS39 to Rab7-RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.
    DOI:  https://doi.org/10.1038/s41467-024-50711-4
  5. Adv Sci (Weinh). 2024 Jun 21. e2309560
    E3 Ubiquitin Ligase RNF13 Suppresses TLR Lysosomal Degradation by Promoting LAMP-1 Proteasomal Degradation.
    Wei Liu, Yuyang Wang, Shuo Liu, Xuan Zhang, Xuetao Cao, Minghong Jiang.
      As a highly organized system, endo-lysosomes play a crucial role in maintaining immune homeostasis. However, the mechanisms involved in regulating endo-lysosome progression and subsequent inflammatory responses are not fully understood. By screening 103 E3 ubiquitin ligases in regulating endo-lysosomal acidification, it is discovered that lysosomal RNF13 inhibits lysosome maturation and promotes inflammatory responses mediated by endosomal Toll-like receptors (TLRs) in macrophages. Mechanistically, RNF13 mediates K48-linked polyubiquitination of LAMP-1 at residue K128 for proteasomal degradation. Upon TLRs activation, LAMP-1 promotes lysosomes maturation, which accelerates lysosomal degradation of TLRs and reduces TLR signaling in macrophages. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA) show increased RNF13 levels and decreased LAMP-1 expression. Accordingly, the immunosuppressive agent hydroxychloroquine (HCQ) can increase the polyubiquitination of RNF13. Taken together, the study establishes a linkage between proteasomal and lysosomal degradation mechanisms for the induction of appropriate innate immune response, and offers a promising approach for the treatment of inflammatory diseases by targeting intracellular TLRs.
    Keywords:  LAMP‐1; RNF13; TLRs; endo‐lysosome; macrophages; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202309560
  6. Metabolism. 2024 Jul 20. pii: S0026-0495(24)00206-3. [Epub ahead of print] 155979
    Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.
    Mengmeng Zhao, Zican Shen, Zihui Zheng, Yao Xu, Jishou Zhang, Jianfang Liu, Shanshan Peng, Jun Wan, Juan-Juan Qin, Menglong Wang.
       AIMS: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy.
    METHODS AND RESULTS: Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice.
    CONCLUSIONS: We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.
    Keywords:  Diabetic cardiomyopathy; Ferroptosis; LGR6; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.metabol.2024.155979
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