bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024‒08‒04
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Research Progress on the Mechanism of Lysosome in Myocardial Ischemia-Reperfusion Injury Based on Autophagy.
  2. Mechanisms of lysosomal tubulation and sorting driven by LRRK2.
  3. TMEM9 activates Rab9-dependent alternative autophagy through interaction with Beclin1.
  4. TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells.
  5. LYSMD proteins promote activation of Rab32-family GTPases for lysosome-related organelle biogenesis.
  6. Western diets and chronic diseases.
  7. Low-Carbohydrate High-Fat Diets, Lipid Levels, and Cardiovascular Risk.
  1. Rev Cardiovasc Med. 2024 Apr;25(4): 113
    Research Progress on the Mechanism of Lysosome in Myocardial Ischemia-Reperfusion Injury Based on Autophagy.
    Yi Li, Hui Wu, Songlin Zhang, Gang Zhou, Dong Zhang, Qingzhuo Yang, Yanfang Liu, Xiaoli Huang.
      In recent years, the interaction of intracellular organelles such as mitochondria and lysosomal functions has attracted increasing attention. Recent evidence suggests that mitochondrion-lysosomal contact plays a key role in regulating lysosomal biogenesis and maintaining cellular homeostasis. Myocardial ischemia and reperfusion will lead to corresponding changes in the autophagy flux in cardiomyocytes, and lysosomes are a key link in the process of autophagy, and the fusion of lysosomes and autophagosomes is an essential link in the occurrence of autophagy. Therefore, the function and homeostasis of lysosomes also undergo different changes during myocardial ischemia and reperfusion. Lysosomal-related biological factors and membrane proteins also play different roles. This article will review the mechanism of lysosomes in myocardial ischemia-reperfusion injury and the research progress of lysosomal-related proteins.
    Keywords:  autophagy; lysosomal membrane protein; lysosome; myocardial ischemia reperfusion injury
    DOI:  https://doi.org/10.31083/j.rcm2504113
  2. Biochem Soc Trans. 2024 Jul 31. pii: BST20240087. [Epub ahead of print]
    Mechanisms of lysosomal tubulation and sorting driven by LRRK2.
    Luis Bonet-Ponce, Jillian H Kluss, Mark R Cookson.
      Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. Lysosomal dysfunction plays a central role in the pathobiology of Parkinson's disease (PD). Gain-of-function mutations in Leucine-rich repeat kinase 2 (LRRK2) cause familial PD and genetic variations in its locus increase the risk of developing the sporadic form of the disease. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by LRRK2), wherein membrane-damaged lysosomes generate tubules sorted into mobile vesicles. Subsequently, these vesicles interact with healthy lysosomes. LYTL is orchestrated by LRRK2 kinase activity, via the recruitment and phosphorylation of a subset of RAB GTPases. Here, we summarize the current understanding of LYTL and its regulation, as well as the unknown aspects of this process.
    Keywords:  Parkinson's disease; RAB proteins; leucine-rich repeat kinase
    DOI:  https://doi.org/10.1042/BST20240087
  3. Cell Mol Life Sci. 2024 Jul 30. 81(1): 322
    TMEM9 activates Rab9-dependent alternative autophagy through interaction with Beclin1.
    Sohyeon Baek, Jae-Woong Chang, Seung-Min Yoo, JeongRim Choo, Sunmin Jung, Jihoon Nah, Yong-Keun Jung.
      Transmembrane protein 9 (TMEM9) is a transmembrane protein that regulates lysosomal acidification by interacting with the v-type ATPase complex. However, the role of TMEM9 in the lysosome-dependent autophagy machinery has yet to be identified. In this study, we demonstrate that the lysosomal protein TMEM9, which is involved in vesicle acidification, regulates Rab9-dependent alternative autophagy through its interaction with Beclin1. The cytosolic domain of TMEM9 interacts with Beclin1 via its Bcl-2-binding domain. This interaction between TMEM9 and Beclin1 dissociates Bcl-2, an autophagy-inhibiting partner, from Beclin1, thereby activating LC3-independent and Rab9-dependent alternative autophagy. Late endosomal and lysosomal TMEM9 apparently colocalizes with Rab9 but not with LC3. Furthermore, we show that multiple glycosylation of TMEM9, essential for lysosomal localization, is essential for its interaction with Beclin1 and the activation of Rab9-dependent alternative autophagy. These findings reveal that TMEM9 recruits and activates the Beclin1 complex at the site of Rab9-dependent autophagosome to induce alternative autophagy.
    Keywords:  Alternative autophagy; Beclin1; Rab9; TMEM9
    DOI:  https://doi.org/10.1007/s00018-024-05366-1
  4. Sci Rep. 2024 Jul 29. 14(1): 17469
    TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells.
    D Wünkhaus, R Tang, K Nyame, N N Laqtom, M Schweizer, A Scotto Rosato, E K Krogsæter, C Wollnik, M Abu-Remaileh, C Grimm, G Hermey, R Kuhn, D Gruber-Schoffnegger, S Markmann.
      Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels in CLN3-KO cells. TRPML1-mediated decrease of storage was TFEB-independent, and we identified TRPML1-mediated enhanced lysosomal exocytosis as a likely mechanism for clearing storage including GPDs. Therefore, ARPE-19 CLN3-KO cells represent a human cell model for CLN3 disease showing many of the described core lysosomal deficits, some of which can be improved using TRPML1 agonists.
    DOI:  https://doi.org/10.1038/s41598-024-67479-8
  5. J Cell Biol. 2024 Oct 07. pii: e202402016. [Epub ahead of print]223(10):
    LYSMD proteins promote activation of Rab32-family GTPases for lysosome-related organelle biogenesis.
    Jinglin Li, Qiuyuan Yin, Nan Xuan, Qiwen Gan, Chaolian Liu, Qian Zhang, Mei Yang, Chonglin Yang.
      Lysosome-related organelles (LROs) are specialized lysosomes with cell type-specific roles in organismal homeostasis. Dysregulation of LROs leads to many human disorders, but the mechanisms underlying their biogenesis are not fully understood. Here, we identify a group of LYSMD proteins as evolutionarily conserved regulators of LROs. In Caenorhabditis elegans, mutations of LMD-2, a LysM domain-containing protein, reduce the levels of the Rab32 GTPase ortholog GLO-1 on intestine-specific LROs, the gut granules, leading to their abnormal enlargement and defective biogenesis. LMD-2 interacts with GLO-3, a subunit of GLO-1 guanine nucleotide exchange factor (GEF), thereby promoting GLO-1 activation. Mammalian homologs of LMD-2, LYSMD1, and LYSMD2 can functionally replace LMD-2 in C. elegans. In mammals, LYSMD1/2 physically interact with the HPS1 subunit of BLOC-3, the GEF of Rab32/38, thus promoting Rab32 activation. Inactivation of both LYSMD1 and LYSMD2 reduces Rab32 activation, causing melanosome enlargement and decreased melanin production in mouse melanoma cells. These findings provide important mechanistic insights into LRO biogenesis and functions.
    DOI:  https://doi.org/10.1083/jcb.202402016
  6. Nat Med. 2024 Jul 31.
    Western diets and chronic diseases.
    Timon E Adolph, Herbert Tilg.
      'Westernization', which incorporates industrial, cultural and dietary trends, has paralleled the rise of noncommunicable diseases across the globe. Today, the Western-style diet emerges as a key stimulus for gut microbial vulnerability, chronic inflammation and chronic diseases, affecting mainly the cardiovascular system, systemic metabolism and the gut. Here we review the diet of modern times and evaluate the threat it poses for human health by summarizing recent epidemiological, translational and clinical studies. We discuss the links between diet and disease in the context of obesity and type 2 diabetes, cardiovascular diseases, gut and liver diseases and solid malignancies. We collectively interpret the evidence and its limitations and discuss future challenges and strategies to overcome these. We argue that healthcare professionals and societies must react today to the detrimental effects of the Western diet to bring about sustainable change and improved outcomes in the future.
    DOI:  https://doi.org/10.1038/s41591-024-03165-6
  7. JACC Adv. 2024 Jun;3(6): 100975
    Low-Carbohydrate High-Fat Diets, Lipid Levels, and Cardiovascular Risk.
    Moriah P Bellissimo, W Gregory Hundley.
      
    Keywords:  atherogenic; cardiac; cholesterol; ketogenic diet; nutrition
    DOI:  https://doi.org/10.1016/j.jacadv.2024.100975
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