bims-lypmec 2026-08-16 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2026–08–16
nine papers selected by
Satoru Kobayashi, New York Institute of Technology

An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
Established and emerging roles of lysosomal dysfunction in cardiac aging.
Initial Molecular Detection of Membrane Damage in Post-Golgi Compartments.
Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.
TRPM2 Promotes Lipophagy Through TFEB and LAL in HFD-Fed Mice.
Metabolism of fructose in the heart favors glycerate production and is linked to cardiac dysfunction in diabetes.
Left ventricular diastolic dysfunction: the missing window for early intervention in diabetic cardiomyopathy.
Polyamines buffer labile iron to suppress ferroptosis.
Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.

Autophagy. 2026 Aug 13. 1-11

An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.

Dale P Corkery, Yao-Wen Wu.

  Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death. Recent advances identify membrane ATG8 conjugation (atg8ylation) as a key process that links damage detection to coordinated lysosomal repair, removal, and regeneration. Beyond its canonical role in macroautophagy, membrane atg8ylation also occurs on preexisting, non-autophagosomal single membranes through Conjugation of ATG8s to Single Membranes (CASM), positioning this pathway as a rapid response to membrane stress. Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling. These ligases convert damage signals into spatially restricted membrane atg8ylation, generating a membrane-associated platform that coordinates multiple downstream pathways. These include ESCRT-dependent membrane repair, ER-lysosome lipid transfer, membrane tubulation, and stress granule formation. When repair fails, membrane atg8ylation regulates lysophagy and activates lysosomal biogenesis and regeneration to restore lysosomal homeostasis. These emerging findings define membrane atg8ylation as a central organizer of membrane quality control rather than a pathway merely confined to macroautophagy. In this review, we summarize the current understanding of how membrane atg8ylation detects lysosomal damage and how this pathway coordinates other lysosomal quality control mechanisms to maintain lysosomal integrity.

Keywords:  CASM; Lysosome; lysosomal membrane integrity; membrane atg8ylation; noncanonical autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2704442
Nat Cardiovasc Res. 2026 Aug;5(8): 675-692

Established and emerging roles of lysosomal dysfunction in cardiac aging.

Yohan Santin, Ilias Simon, Angelo Parini, Frank Lezoualc'h, Elena Sommariva.

Cardiac aging is a central biological process underlying most cardiovascular diseases. Lysosomes, once regarded as terminal degradative compartments, are now recognized as dynamic metabolic and signaling hubs whose dysfunction has profound consequences for the aging heart. Human lysosomal storage disorders provide compelling evidence that isolated lysosomal defects are sufficient to cause early cardiomyopathy, underscoring the myocardium's exceptional dependence on sustained lysosomal competence. In physiological aging, impaired autophagy is the most apparent manifestation of lysosomal decline but represents only one facet of a broader network regulating nutrient sensing, ion and lipid homeostasis, receptor trafficking, exocytosis/secretion and inter-organelle communication. Here, we review established and emerging lysosome-dependent mechanisms across the hallmarks of cardiac aging, highlighting lysosomes as potential upstream drivers of this process. We discuss key knowledge gaps and therapeutic strategies aimed at restoring lysosomal function, positioning lysosomes as central and actionable targets for preserving cardiac resilience with age.

DOI: https://doi.org/10.1038/s44161-026-00853-z
Cells. 2026 Jul 30. pii: 1375. [Epub ahead of print]15(15):

Initial Molecular Detection of Membrane Damage in Post-Golgi Compartments.

Yoko Shiba, Nana Saito.

  Mammalian cells contain numerous membrane-bound organelles, of which endosomes serve as the initial destination for endocytosed molecules. Therapeutic agents are also internalized by cells and transported to endosomes or phagosomes and subsequently delivered to lysosomes for degradation. Therefore, these agents require drug delivery systems (DDSs) that enable their escape from endosomes into the cytosol before lysosomal degradation; however, endosomal escape is a major limitation of current DDSs. Studies of bacterial phagosomal escape have revealed mechanisms by which host cells detect damage to organelle membranes. These membrane damage-sensing molecules also recognize membrane damage caused by artificial DDSs or physical energy-based insults. In this review, we summarize the molecular mechanisms underlying the early stages of membrane damage in the plasma membrane, lysosomes and bacteria-containing vacuoles (BCVs) to better understand the early stages of endosomal membrane damage in the absence of pathogens. We summarize recent advances in galectins, endosomal sorting complexes required for transport (ESCRT) complexes, sphingomyelin, stress granules, and phosphatidylinositol 4-phosphate (PI4P) at membrane contact sites, as well as annexins. We also discuss the recruitment kinetics of these molecules to damaged membranes. Although the recruitment kinetics vary depending on cell type and experimental conditions, this information provides a timeframe for the events following membrane damage, including damage sensing, membrane repair, and degradation of damaged organelles. We also discuss a potential fourth event, fusion between the plasma membrane and endosomes or lysosomes for membrane repair in the annexin section. Finally, we summarize approaches for inducing "sterile" endosomal membrane damage. Future development of these approaches may facilitate the design of novel DDSs and physical energy-based strategies for manipulating specific organelles.

Keywords:  ESCRT; PI4P; annexins; galectin; membrane damage; membrane repair by fusion; sphingomyelin

DOI:  https://doi.org/10.3390/cells15151375
FEBS Lett. 2026 Aug 10.

Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.

Rainer Ettelt, Ana-Maria Sandru, Georg Vucak, Sebastian Didusch, Biljana Riemelmoser, Karin Ehrenreiter, Markus Hartl, Lukas A Huber, Manuela Baccarini.

  Lysosomes are dynamic organelles regulating metabolic signaling by recruiting cytosolic molecules to protein platforms on their limiting membrane. We used proximity labeling to define interactors and vicinal proteins of LAMTOR3, a component of the Ragulator scaffold that controls mTORC1 signaling and lysosome positioning. The screen has yielded several previously unappreciated interactors, including an actin remodeling network. Here, we characterize the RhoGEF PLEKHG3 as a LAMTOR3 vicinal protein colocalizing with peripheral lysosomes and cortical F-actin at focal adhesion sites. Forced peripheral dispersion of lysosomes drives PLEKHG3 accumulation at focal adhesions and decreases protrusive activity in both wild-type and PLEKHG3-deficient cells. Thus, lysosome positioning governs both PLEKHG3 localization and protrusive activity, yet the protrusion changes can occur independently of PLEKHG3.

Keywords:  LAMTOR; PLEKHG3; cell motility; cytoskeleton; focal adhesions; lysosomes

DOI:  https://doi.org/10.1002/1873-3468.70428
Cells. 2026 Jul 28. pii: 1361. [Epub ahead of print]15(15):

TRPM2 Promotes Lipophagy Through TFEB and LAL in HFD-Fed Mice.

Fan Ying, Duan Zhuo, Shaobo Zhou, Liwen Jiang, Xiaoqiang Yao.

  An abnormality of Ca2+ signaling may aggravate lipid accumulation in steatotic hepatocytes, leading to non-alcoholic fatty liver disease. However, the molecular identity of Ca2+-permeable channels and the mechanism of involvement of these channels in steatotic hepatocytes are not well-studied. In the present study, we investigated the role of a Ca2+-permeable channel TRPM2 in lipid metabolism in steatotic hepatocytes. A mouse model of non-alcoholic fatty liver disease was established by high-fat-diet feeding. Fat accumulation, fibrosis, lipophagic indexes, TFEB and lysosomal acid lipase in the liver tissue and/or hepatocytes were compared between TRPM2-knockout mice and wild-type mice. Knockout of the TRPM2 gene aggravated liver fat accumulation and fibrosis. Mechanistically, the TRPM2 knockout impaired the lipophagic process, decreased lysosomal abundance and attenuated lysosomal/autolysosomal acidification in mouse hepatocytes. Furthermore, the TRPM2 knockout reduced TFEB expression and its nuclear translation and also reduced the expression/activity of lysosomal acid lipase. These data demonstrate that TRPM2 deficiency may reduce lipophagy via its action on TFEB and lysosomal acid lipase, consequently contributing to liver steatosis and NAFLD under high-fat feeding conditions.

Keywords:  TRPM2 channels; lipophagy; lysosomal acid lipase; lysosomal biogenesis

DOI:  https://doi.org/10.3390/cells15151361
J Mol Cell Cardiol. 2026 Aug 13. pii: S0022-2828(26)00121-5. [Epub ahead of print]218 121-129

Metabolism of fructose in the heart favors glycerate production and is linked to cardiac dysfunction in diabetes.

Marco Annandale, Dominic Lachance, Isabelle F Robillard, George Guo, Xun Li, Parisa Koutsifeli, Lorna J Daniels, Erica Zarate, Angus C Grey, Lea M D Delbridge, Matthieu Ruiz, Christine Des Rosiers, Kimberley M Mellor.

  Increased cardiac risk in diabetes has been linked to disturbances in myocardial metabolism. Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. The goal of this study was to assess myocardial capacity for fructose metabolism and evaluate the time-course of cardiac fructose accumulation relative to the emergence of cardiac functional impairment in diabetic rats. Cardiac capability for fructose metabolism to support function was demonstrated in ex vivo working mouse hearts perfused with 11 mM fructose. Using isotope-labeled fructose [U13C], we observed 13C enrichment into downstream metabolites glyceraldehyde, glycerate, pyruvate, lactate, and mitochondrial acetyl-CoA in perfused working mouse hearts. Metabolite profiling demonstrated that relative to glucose, myocardial fructose metabolism favored glycerate production. In diabetic rats (streptozotocin, 55 mg/kg), cardiac fructose elevation was evident prior to the onset of cardiac dysfunction. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies key fructose-derived metabolites. The finding that cardiac fructose elevation precedes functional impairment supports the contention that fructose may be an early instigator of diabetic cardiomyopathy and further investigation is now warranted. NEW AND NOTEWORTHY (<75 WORDS): Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies that cardiac fructose metabolism favors production of glycerate. In diabetes, cardiac fructose elevation precedes functional impairment supporting the contention that fructose may be an early instigator of diabetic cardiomyopathy.

Keywords:  Cardiac metabolism; Diabetic cardiomyopathy; Isotope tracing; Metabolomics

DOI:  https://doi.org/10.1016/j.yjmcc.2026.08.003
Front Endocrinol (Lausanne). 2026 ;17 1921804

Left ventricular diastolic dysfunction: the missing window for early intervention in diabetic cardiomyopathy.

Yuting Lin, Yebin Xia, Jinjian Guo.



Keywords:  cardio-metabolic disease; diabetic cardiomyopathy; heart failure with preserved ejection fraction; left ventricular diastolic dysfunction; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fendo.2026.1921804
Cell. 2026 Aug 14. pii: S0092-8674(26)00872-X. [Epub ahead of print]

Polyamines buffer labile iron to suppress ferroptosis.

Pushkal Sharma, Heather R Keys, Ryan P Mansell, Jillian Stark, Louisa Girard, Christalyn Ausler, Rachel Anderson, Sebastian Müller, Shinya Imada, Ivan S Pires, Tenzin Kunchok, Millenia Waite, Bingbing Yuan, Amy Deik, Luke Ferro, Paula T Hammond, Raphaël Rodriguez, Maria-Eirini Pandelia, Whitney S Henry, Ankur Jain.

  Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

Keywords:  GPX4; ferroptosis; genetically encoded iron sensor; iron homeostasis; labile iron pool; polyamines; redox-active iron; spermidine; spermine

DOI:  https://doi.org/10.1016/j.cell.2026.07.040
Sci Adv. 2026 Aug 14. 12(33): eaeh0657

Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.

Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li.

Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.

DOI: https://doi.org/10.1126/sciadv.aeh0657