bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023–12–10
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Transcription Factor EB-Mediated Lysosomal Function Regulation for Determining Stem Cell Fate under Metabolic Stress.
  2. mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
  3. Complete set of the Atg8-E1-E2-E3 conjugation machinery forms an interaction web that mediates membrane shaping.
  4. Transmembrane coupling of liquid-like protein condensates.
  5. Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.
  6. Glycine recalibrates iron homeostasis of lens epithelial cells by blocking lysosome-dependent ferritin degradation.
  7. RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy.
  1. Mol Cells. 2023 Dec 31. 46(12): 727-735
    Transcription Factor EB-Mediated Lysosomal Function Regulation for Determining Stem Cell Fate under Metabolic Stress.
    Chang Woo Chae, Young Hyun Jung, Ho Jae Han.
      Stem cells require high amounts of energy to replicate their genome and organelles and differentiate into numerous cell types. Therefore, metabolic stress has a major impact on stem cell fate determination, including self-renewal, quiescence, and differentiation. Lysosomes are catabolic organelles that influence stem cell function and fate by regulating the degradation of intracellular components and maintaining cellular homeostasis in response to metabolic stress. Lysosomal functions altered by metabolic stress are tightly regulated by the transcription factor EB (TFEB) and TFE3, critical regulators of lysosomal gene expression. Therefore, understanding the regulatory mechanism of TFEB-mediated lysosomal function may provide some insight into stem cell fate determination under metabolic stress. In this review, we summarize the molecular mechanism of TFEB/TFE3 in modulating stem cell lysosomal function and then elucidate the role of TFEB/TFE3-mediated transcriptional activity in the determination of stem cell fate under metabolic stress.
    Keywords:  lysosomal function; metabolic stress; stem cell fate; transcription factor EB
    DOI:  https://doi.org/10.14348/molcells.2023.0143
  2. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00417-5. [Epub ahead of print]35(12): 2097-2099
    mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
    Estela Jacinto.
      Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.006
  3. Nat Struct Mol Biol. 2023 Dec 06.
    Complete set of the Atg8-E1-E2-E3 conjugation machinery forms an interaction web that mediates membrane shaping.
    Jahangir Md Alam, Tatsuro Maruyama, Daisuke Noshiro, Chika Kakuta, Tetsuya Kotani, Hitoshi Nakatogawa, Nobuo N Noda.
      Atg8, a ubiquitin-like protein, is conjugated with phosphatidylethanolamine (PE) via Atg7 (E1), Atg3 (E2) and Atg12-Atg5-Atg16 (E3) enzymatic cascade and mediates autophagy. However, its molecular roles in autophagosome formation are still unclear. Here we show that Saccharomyces cerevisiae Atg8-PE and E1-E2-E3 enzymes together construct a stable, mobile membrane scaffold. The complete scaffold formation induces an in-bud in prolate-shaped giant liposomes, transforming their morphology into one reminiscent of isolation membranes before sealing. In addition to their enzymatic roles in Atg8 lipidation, all three proteins contribute nonenzymatically to membrane scaffolding and shaping. Nuclear magnetic resonance analyses revealed that Atg8, E1, E2 and E3 together form an interaction web through multivalent weak interactions, where the intrinsically disordered regions in Atg3 play a central role. These data suggest that all six Atg proteins in the Atg8 conjugation machinery control membrane shaping during autophagosome formation.
    DOI:  https://doi.org/10.1038/s41594-023-01132-2
  4. Nat Commun. 2023 Dec 04. 14(1): 8015
    Transmembrane coupling of liquid-like protein condensates.
    Yohan Lee, Sujin Park, Feng Yuan, Carl C Hayden, Liping Wang, Eileen M Lafer, Siyoung Q Choi, Jeanne C Stachowiak.
      Liquid-liquid phase separation of proteins occurs on both surfaces of cellular membranes during diverse physiological processes. In vitro reconstitution could provide insight into the mechanisms underlying these events. However, most existing reconstitution techniques provide access to only one membrane surface, making it difficult to probe transmembrane phenomena. To study protein phase separation simultaneously on both membrane surfaces, we developed an array of freestanding planar lipid membranes. Interestingly, we observed that liquid-like protein condensates on one side of the membrane colocalized with those on the other side, resulting in transmembrane coupling. Our results, based on lipid probe partitioning and mobility of lipids, suggest that protein condensates locally reorganize membrane lipids, a process which could be explained by multiple effects. These findings suggest a mechanism by which signals originating on one side of a biological membrane, triggered by protein phase separation, can be transferred to the opposite side.
    DOI:  https://doi.org/10.1038/s41467-023-43332-w
  5. J Diabetes. 2023 Dec 05.
    Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.
    Yueran Zhou, Zequn Zheng, Shenglin Wu, Jinxiu Zhu.
      The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin-like modifier], a post-translational modification of proteins, and its associated ubiquitin-proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart. Specifically, the expression of ubiquitin-conjugating enzyme E2 (Ubc9), the only SUMO-E2 enzyme, exerts a positive regulatory effect on autophagy in cardiomyocytes with potential cardioprotective effects. This review focuses on the role that autophagy plays in DCM and the potential for Ubc9-regulated autophagy pathways to ameliorate DCM, highlighting the potential of Ubc9 as an interventional target in DCM and providing new insights into the pathogenesis of the disease.
    Keywords:  Ubc9; autophagy; diabetic cardiomyopathy; target
    DOI:  https://doi.org/10.1111/1753-0407.13511
  6. Free Radic Biol Med. 2023 Nov 30. pii: S0891-5849(23)01121-8. [Epub ahead of print]210 258-270
    Glycine recalibrates iron homeostasis of lens epithelial cells by blocking lysosome-dependent ferritin degradation.
    Ludi Wang, Jinxia Liu, Dongyue Ma, Xinyu Zhi, Luo Li, Shanjiao Li, Weijia Li, Jiangyue Zhao, Yu Qin.
      One of the major pathological processes in cataracts has been identified as ferroptosis. However, studies on the iron metabolism mechanism in lens epithelial cells (LECs) and the methods of effectively alleviating ferroptosis in LECs are scarce. Along these lines, we found that in the ultraviolet radiation b (UVB) induced cataract model in vitro and in vivo, the ferritin of LECs is over-degraded by lysosomes, resulting in the occurrence of iron homeostasis disorder. Glycine can affect the ferritin degradation through the proton-coupled amino acid transporter (PAT1) on the lysosome membrane, further upregulating the content of nuclear factor erythrocyte 2 related factor 2 (Nrf2) to reduce the damage of LECs from two aspects of regulating iron homeostasis and alleviating oxidative stress. By co-staining, we further demonstrate that there is a more sensitive poly-(rC)-binding protein 2 (PCBP2) transportation of iron ions in LECs after UVB irradiation. Additionally, this study illustrated the increased expression of nuclear receptor coactivator 4 (NCOA4) in NRF2-KO mice, indicating that Nrf2 may affect ferritin degradation by decreasing the expression of NCOA4. Collectively, glycine can effectively regulate cellular iron homeostasis by synergistically affecting the lysosome-dependent ferritin degradation and PCBP2-mediated ferrous ion transportation, ultimately delaying the development of cataracts.
    Keywords:  Cataract; FTH1; Glycine; Iron homeostasis; Lysosome
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.020
  7. Commun Biol. 2023 Dec 05. 6(1): 1229
    RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy.
    Miriam Krumbein, Froma Oberman, Yuval Cinnamon, Mordechai Golomb, Dalit May, Gilad Vainer, Vitali Belzer, Karen Meir, Irina Fridman, Johannes Haybaeck, Gerhard Poelzl, Izhak Kehat, Ronen Beeri, Sonja M Kessler, Joel K Yisraeli.
      The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.
    DOI:  https://doi.org/10.1038/s42003-023-05547-x
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