bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023–09–03
nine papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Lysosomal glucose sensing and glycophagy in metabolism.
  2. TECPR1 helps bridge the CASM during lysosome damage.
  3. Atl (atlastin) regulates mTor signaling and autophagy in Drosophila muscle through alteration of the lysosomal network.
  4. Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
  5. A yeast vacuolar pH 'heartbeat' coordinates amino acid metabolism and the cell cycle.
  6. Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
  7. Cardiac gene therapy rescues diabetic cardiomyopathy and lowers blood glucose.
  8. Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.
  9. Mind the gap: Methods to study membrane contact sites.
  1. Trends Endocrinol Metab. 2023 Aug 24. pii: S1043-2760(23)00152-2. [Epub ahead of print]
    Lysosomal glucose sensing and glycophagy in metabolism.
    Melina C Mancini, Robert C Noland, J Jason Collier, Susan J Burke, Krisztian Stadler, Timothy D Heden.
      Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism is unrefined. This review will highlight the role of the lysosome in glucose metabolism with a focus on lysosomal glucose and glycogen sensing, glycophagy, and lysosomal glucose transport and how these processes impact autophagy and energy metabolism. Additionally, the role of lysosomal glucose metabolism in genetic and metabolic diseases will be briefly discussed.
    Keywords:  autophagy; carbohydrate sensing; glycogen; nutrient sensing
    DOI:  https://doi.org/10.1016/j.tem.2023.07.008
  2. EMBO J. 2023 Aug 28. e115210
    TECPR1 helps bridge the CASM during lysosome damage.
    Oliver Florey.
      Maintaining the integrity of the endolysosomal system is of great importance for cellular homeostasis. Recent work published in The EMBO Journal and EMBO Reports reveals a novel role for the protein TECPR1 as a sensor for stressed membranes and regulator of lysosomal membrane repair.
    DOI:  https://doi.org/10.15252/embj.2023115210
  3. Autophagy. 2023 Aug 30. 1-20
    Atl (atlastin) regulates mTor signaling and autophagy in Drosophila muscle through alteration of the lysosomal network.
    Saurabh Srivastav, Kevin van der Graaf, Pratibha Singh, Alloysius Budi Utama, Matthew D Meyer, James A McNew, Michael Stern.
       ABBREVIATIONS: atl atlastin; ALR autophagic lysosome reformation; ER endoplasmic reticulum; GFP green fluorescent protein; HSP hereditary spastic paraplegia; Lamp1 lysosomal associated membrane protein 1 PolyUB polyubiquitin; RFP red fluorescent protein; spin spinster; mTor mechanistic Target of rapamycin; VCP valosin containing protein.
    Keywords:  ATG8; Hereditary Spastic Paraplegia; LAMP1; Neurodegeneration; endosome; protein aggregates; rab7
    DOI:  https://doi.org/10.1080/15548627.2023.2249794
  4. Mol Cell. 2023 Aug 24. pii: S1097-2765(23)00640-8. [Epub ahead of print]
    Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
    Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian.
      The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.
    Keywords:  AhR; cancer therapy; cysteine; cystine; ferroptosis; lysosome; mRNA; nutrient stress
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.004
  5. Nat Metab. 2023 Aug 28.
    A yeast vacuolar pH 'heartbeat' coordinates amino acid metabolism and the cell cycle.
    Patricia M Kane.
      
    DOI:  https://doi.org/10.1038/s42255-023-00875-y
  6. Nat Metab. 2023 Aug 28.
    Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
    Voytek Okreglak, Rachel Ling, Maria Ingaramo, Nathaniel H Thayer, Alfred Millett-Sikking, Daniel E Gottschling.
      Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide. The vacuolar pH dynamics require the uptake of extracellular amino acids and activity of TORC1, the v-ATPase and the cycling of the vacuolar specific lipid phosphatidylinositol 3,5-bisphosphate, which is regulated by the cyclin-dependent kinase Pho85 (CDK5 in mammals). Vacuolar pH regulation enables amino acid sequestration and mobilization from the organelle, which is important for mitochondrial function, ribosome homeostasis and cell size control. Collectively, our data provide a new paradigm for the use of dynamic pH-dependent amino acid compartmentalization during cell growth/division.
    DOI:  https://doi.org/10.1038/s42255-023-00872-1
  7. JCI Insight. 2023 Aug 24. pii: e166713. [Epub ahead of print]
    Cardiac gene therapy rescues diabetic cardiomyopathy and lowers blood glucose.
    Jing Li, Bradley Richmond, Ahmad A Cluntun, Ryan Bia, Maureen A Walsh, Kikuyo Shaw, J David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M Shaw, TingTing Hong.
      Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.
    Keywords:  Cardiology; Cell Biology; Gene therapy; Glucose metabolism; Heart failure
    DOI:  https://doi.org/10.1172/jci.insight.166713
  8. Exp Mol Med. 2023 Sep 01.
    Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.
    Soo-Jin Oh, Kihyoun Park, Seong Keun Sonn, Goo Taeg Oh, Myung-Shik Lee.
      Mitophagy is an excellent example of selective autophagy that eliminates damaged or dysfunctional mitochondria, and it is crucial for the maintenance of mitochondrial integrity and function. The critical roles of autophagy in pancreatic β-cell structure and function have been clearly shown. Furthermore, morphological abnormalities and decreased function of mitochondria have been observed in autophagy-deficient β-cells, suggesting the importance of β-cell mitophagy. However, the role of authentic mitophagy in β-cell function has not been clearly demonstrated, as mice with pancreatic β-cell-specific disruption of Parkin, one of the most important players in mitophagy, did not exhibit apparent abnormalities in β-cell function or glucose homeostasis. Instead, the role of mitophagy in pancreatic β-cells has been investigated using β-cell-specific Tfeb-knockout mice (TfebΔβ-cell mice); Tfeb is a master regulator of lysosomal biogenesis or autophagy gene expression and participates in mitophagy. TfebΔβ-cell mice were unable to adaptively increase mitophagy or mitochondrial complex activity in response to high-fat diet (HFD)-induced metabolic stress. Consequently, TfebΔβ-cell mice exhibited impaired β-cell responses and further exacerbated metabolic deterioration after HFD feeding. TFEB was activated by mitochondrial or metabolic stress-induced lysosomal Ca2+ release, which led to calcineurin activation and mitophagy. After lysosomal Ca2+ release, depleted lysosomal Ca2+ stores were replenished by ER Ca2+ through ER→lysosomal Ca2+ refilling, which supplemented the low lysosomal Ca2+ capacity. The importance of mitophagy in β-cell function was also demonstrated in mice that developed β-cell dysfunction and glucose intolerance after treatment with a calcineurin inhibitor that hampered TFEB activation and mitophagy.
    DOI:  https://doi.org/10.1038/s12276-023-01055-4
  9. Exp Cell Res. 2023 Aug 24. pii: S0014-4827(23)00304-X. [Epub ahead of print] 113756
    Mind the gap: Methods to study membrane contact sites.
    Tanveera Rounaque Sarhadi, Janhavee Shirish Panse, Shirisha Nagotu.
      Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is essential for the exchange of metabolites and their communication. These functional apposition sites are termed membrane contact sites. Dynamic membrane contact sites between various sub-cellular structures such as mitochondria, endoplasmic reticulum, peroxisomes, Golgi apparatus, lysosomes, lipid droplets, plasma membrane, endosomes, etc. have been reported in various model systems. The burgeoning area of research on membrane contact sites has witnessed several manuscripts in recent years that identified the contact sites and components involved. Several methods have been developed to identify, measure and analyze the membrane contact sites. In this manuscript, we aim to discuss important methods developed to date that are used to study membrane contact sites.
    Keywords:  Biotinylation; Membrane contact sites; Microscopy; Organelles; Proximity
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113756
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