bims-mecosi Biomed News
on Membrane contact sites
Issue of 2022–01–02
two papers selected by
Verena Kohler, Stockholm University
  1. MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51.
  2. Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells.
  1. J Biochem. 2021 Dec 29. pii: mvab153. [Epub ahead of print]
    MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51.
    Naoki Ito, Takara Takahashi, Isshin Shiiba, Shun Nagashima, Ryoko Inatome, Shigeru Yanagi.
      The transfer of phospholipids from the endoplasmic reticulum to mitochondria via the mitochondria-endoplasmic reticulum (ER) contact site (MERCS) is essential for maintaining mitochondrial function and integrity. Here, we identified RMDN3/PTPIP51, possessing phosphatidic acid (PA)-transfer activity, as a neighboring protein of the mitochondrial E3 ubiquitin ligase MITOL/MARCH5 by proximity-dependent biotin labeling using APEX2. We found that MITOL interacts with and ubiquitinates RMDN3. Mutational analysis identified lysine residue 89 in RMDN3 as a site of ubiquitination by MITOL. Loss of MITOL or the substitution of lysine 89 to arginine in RMDN3 significantly reduced the PA-binding activity of RMDN3, suggesting that MITOL regulates the transport of PA to mitochondria by activating RMDN3. Our findings imply that ubiquitin signaling regulates phospholipid transport at the MERCS.
    Keywords:  E3 ubiquitin ligase; MITOL; RMDN3; mitochondria-ER contact site; phospholipid
    DOI:  https://doi.org/10.1093/jb/mvab153
  2. Front Cell Dev Biol. 2021 ;9 790568
    Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells.
    Fernanda Cabrera-Reyes, Claudia Parra-Ruiz, María Isabel Yuseff, Silvana Zanlungo.
      Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.
    Keywords:  B cell activation and membrane contact sites (MCSs); CD36; cathepsins; gaucher disease (GD); lysosomal dysfunction; niemann-pick type C (NPC); obesity
    DOI:  https://doi.org/10.3389/fcell.2021.790568
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