bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–06–08
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. The TECPR1:ATG5-ATG12 complex conjugates LC3/ATG8 to damaged lysosomes that expose luminal glycans in response to osmotic imbalance.
  2. ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.
  3. Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
  4. Myristoylation of TMEM106B by NMT1/2 regulates TMEM106B trafficking and turnover.
  5. Intracellular pH Regulation in Ventricular Myocytes: Implications for Cardiac Health and Disease.
  6. Modulation of cardiac fatty acid or glucose oxidation to treat heart failure in preclinical models: a systematic review and meta-analysis.
  7. Why the Diabetic Heart Is Fatty.
  1. Autophagy Rep. 2025 ;4(1): 2476218
    The TECPR1:ATG5-ATG12 complex conjugates LC3/ATG8 to damaged lysosomes that expose luminal glycans in response to osmotic imbalance.
    Yingxue Wang, Matthew Jefferson, Maria Ramos, Matthew Whelband, Kristin Kreuzer, Grace Khuu, Michael Lazarou, James Mccoll, James Lazenby, Cynthia B Whitchurch, Paul Verkade, Ulrike Mayer, Thomas Wileman.
      Hydrolytic enzymes within lysosomes maintain cell and tissue homoeostasis by degrading macromolecules delivered by endocytosis and autophagy. The release of lysosomal enzymes into the cytosol can induce apoptosis and "lysosome-dependent cell death" making it important for damaged lysosomes to be repaired or removed. Extensive lysosome damage exposes luminal sugars to galectin-dependent autophagy pathways that use ATG16L1:ATG5-ATG12 complex to conjugate LC3/ATG8 to autophagosomes to facilitate removal by lysophagy. Sphingomyelin exposed on stressed lysosomes recruits the lysosome tethering protein TECPR1 (tectonin beta propeller repeat-containing protein) allowing an alternative TECRP1:ATG5-ATG12 complex to conjugate LC3 directly to lysosomes. Here we have used cells lacking ATG16L1 to follow the recruitment of TECPR1, galectin-3 and LC3/ATG8 to lysosomes in response to osmotic imbalance induced by chloroquine. TECPR1 was recruited to swollen lysosomes that exposed sphingomyelin. LC3II was absent from swollen lysosomes but located to small puncta that contained the V-ATPase and LAMP1. The presence of galectin-3 and PI4P in the small LC3 puncta suggested that the TECPR1:ATG5-ATG12 complex conjugates LC3 to lysosome remnants that have ruptured in response to osmotic imbalance.
    Keywords:  ATG16L1; Autophagy; LC3/ATG8; TECPR1; chloroquine; galectin 3; lysosome damage; osmotic stress; sphingomyelin
    DOI:  https://doi.org/10.1080/27694127.2025.2476218
  2. Dev Cell. 2025 May 27. pii: S1534-5807(25)00318-1. [Epub ahead of print]
    ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.
    Stefano De Tito, Eugenia Almacellas, Daniel Dai Yu, Emily Millard, Wenxin Zhang, Cecilia de Heus, Christophe Queval, Javier H Hervás, Enrica Pellegrino, Ioanna Panagi, Ditte Fogde, Teresa L M Thurston, Judith Klumperman, Maximiliano Gutierrez, Sharon A Tooze.
      Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving endoplasmic reticulum (ER)-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P), and oxysterol-binding protein-like proteins (OSBPLs) lipid transfer proteins. PI4K2A localizes to the trans-Golgi network and endosomes, yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing OSBPL-dependent lipid transfer and promoting the retrieval of ATG9A vesicles through the recruitment of the adaptor protein complex-3 (AP-3). Our results identify a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.
    Keywords:  AP-3; ARFIP2; ATG9A; PI4K2A; PI4P; autophagy; lysosomal damage; lysosome; membrane trafficking
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.007
  3. Nat Commun. 2025 Jun 05. 16(1): 5209
    Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
    Ran Chen, Bin Liu, Dawid Jaślan, Lucija Kucej, Veronika Kudrina, Belinda Warnke, Yvonne E Klingl, Arnas Petrauskas, Sandra Prat Castro, Kenji Maeda, Christian Grimm, Marja Jäättelä.
      The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how lysosomes replenish their calcium stores in placental mammals has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the cytosol. These data indicate that in addition to its previously identified role in the glycosylation of proteins and lipids in the Golgi, a fraction of TMEM165 localizes on the lysosomal limiting membrane, where its putative calcium/proton antiporter activity plays an essential role in the regulation of intracellular ion homeostasis and cell survival.
    DOI:  https://doi.org/10.1038/s41467-025-60349-5
  4. J Biol Chem. 2025 May 30. pii: S0021-9258(25)02172-6. [Epub ahead of print] 110322
    Myristoylation of TMEM106B by NMT1/2 regulates TMEM106B trafficking and turnover.
    Alexander Lacrampe, Dan Hou, Isis G Perez, Belvin Gong, Natalia Franco-Hernandez, Angie Yee, Wenzhe Chen, Maxime Ah Young-Chapon, Hening Lin, Fenghua Hu.
      TMEM106B, a type II transmembrane protein localized on the lysosomal membrane, has been identified as a central player in neurodegeneration and brain aging during the past decade. TMEM106B variants that increase TMEM106B expression levels are linked to several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). Additionally, the C-terminal lumenal fragment of TMEM106B was recently shown to form amyloid fibrils during aging and neurodegeneration. However, the mechanisms regulating TMEM106B levels are not well understood. Here we show that TMEM106B is myristoylated by NMT1/2 enzymes at its glycine 2 α-amino group and its lysine 3 ε-amino group. Myristoylation decreases TMEM106B levels by promoting its lysosomal degradation. Furthermore, we demonstrate that TMEM106B C-terminal fragments (CTFs) can be detected under physiological conditions and the levels of CTFs are regulated by myristoylation and lysosomal activities. In addition, we show that non-myristoylated TMEM106B accumulates on the cell surface, indicating that myristoylation affects TMEM106B trafficking within the cell. Taken together, these findings suggest that TMEM106B myristoylation is an important mechanism regulating its function, trafficking, and turnover.
    Keywords:  Lysosome; Myristoylation; NMT1/2; TMEM106B
    DOI:  https://doi.org/10.1016/j.jbc.2025.110322
  5. Circ Res. 2025 Jun 06. 136(12): 1636-1656
    Intracellular pH Regulation in Ventricular Myocytes: Implications for Cardiac Health and Disease.
    Alejandro Orlowski, Romina Alejandra Di Mattia, Ernesto Alejandro Aiello.
      Intracellular pH must be maintained within the physiological range (7.15-7.25) to ensure cellular homeostasis. In the heart, excitation-contraction coupling is closely dependent on intracellular pH because its proper regulation helps the correct management of intracellular Ca2+. In addition, it is important to know the spatial distribution of intracellular pH microdomains because it helps us to better understand the compartmentalized regulation of different channels, transporters, and enzymes. Therefore, maintaining cardiac intracellular pH at physiological levels is of crucial importance for cardiac health. This function is performed by transporters and channels that ensure the transport of H+ equivalents to both sides of the sarcolemma. In the cardiac myocyte, 3 alkalizing mechanisms are expressed in the sarcolemma, the NHE1 (Na+/H+ exchanger 1), the NBC (Na+/HCO3- cotransporter, represented by 2 different isoforms; NBCn1 [electrically neutral sodium/bicarbonate cotransporter 1] and NBCe1 [electrogenic sodium/bicarbonate cotransporter 1]), and a proton channel (HVCN1 [hydrogen voltage-gated proton channel 1]; IH+), and 2 acidifying transporters, the Cl-/HCO3- exchanger (AE [anion exchanger], mainly AE1, AE2, and AE3) and Slc26a6 (solute carrier family 26 member A6), which, in the heart, predominantly exchanges Cl-/HCO3- and Cl-/OH-. The presence of a lactate-H+ cotransport (MCT [monocarboxylate transporter]) has also been described, which operates in either efflux or influx mode. The overstimulation of NHE1 and NBCn1, and the dysfunction of NBCe1 have been associated with the development of maladaptive cardiac hypertrophy. On the other hand, the sudden stimulation of these transporters, which occurs during reperfusion after ischemia, greatly contributes to the cardiac injury of this insult to the myocardium. The alteration of the normal functioning of the acidifying mechanisms has also been implicated in these pathologies. This review focuses on the role that these mechanisms play in healthy and diseased hearts.
    Keywords:  cardiac hypertrophy; cardiac myocytes; intracellular pH; myocardial ischemia; transporters
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.325386
  6. Commun Med (Lond). 2025 Jun 04. 5(1): 213
    Modulation of cardiac fatty acid or glucose oxidation to treat heart failure in preclinical models: a systematic review and meta-analysis.
    Tom Fischer, Christina Schenkl, Estelle Heyne, Peter Schlattmann, Torsten Doenst, P Christian Schulze, T Dung Nguyen.
       BACKGROUND: Current expert opinion on cardiac metabolism in heart failure (HF) suggests that inhibiting cardiac fatty acid oxidation (FAO) or stimulating cardiac glucose oxidation (GO) can improve heart function. However, systematic evidence is lacking, and contradictory data exist. Therefore, we conducted a comprehensive meta-analysis to assess the effects of modulating myocardial GO or FAO on heart function.
    METHODS: We screened MEDLINE via Ovid, Scopus, and Web of Science until March 02, 2024 for interventional studies reporting significant changes in cardiac GO or FAO in established animal models of HF, such as ischemia-reperfusion, pressure overload, rapid pacing, and diabetic cardiomyopathy. We employed multivariate analysis (four-level random-effects model) to enclose all measures of heart function. Additionally, we used meta-regression to explore heterogeneity and contour-enhanced funnel plots to assess publication bias. The protocol is registered on PROSPERO (CRD42023456359).
    RESULTS: Of a total of 10,628 studies screened, 103 studies are included. Multivariate meta-analysis reveals that enhancing cardiac GO considerably restores cardiac function (Hedges' g = 1.03; 95% CI: 0.79-1.26; p < 0.001). Interestingly, interventions associated with reduced myocardial FAO show neutral effects (Hedges' g = 0.24; 95% CI: -0.57-1.05; p = 0.557), while those augmenting myocardial FAO markedly improve function (Hedges' g = 1.17; 95% CI: 0.58-1.76; p < 0.001).
    CONCLUSIONS: Our data underscore the role of cardiac metabolism in treating HF. Specifically, these results suggest that stimulating either myocardial FAO or GO may considerably improve cardiac function. Furthermore, these results question the current notion that inhibition of cardiac FAO is protective.
    DOI:  https://doi.org/10.1038/s43856-025-00924-5
  7. Circ Res. 2025 Jun 06. 136(12): 1561-1563
    Why the Diabetic Heart Is Fatty.
    Yijun Yang, Zolt Arany.
      
    Keywords:  Editorials; calcium signaling; diabetic cardiomyopathies; fatty acids; insulin resistance
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326677
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒08 at 13:06.