bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–11–08
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Lysosomal alkalinization: a convergent mechanism in lysosomal storage disorders and classical neurodegenerative diseases.
  2. Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.
  3. Live-cell imaging of inter-organelle contacts using an integrated dimerization-dependent fluorescent protein reporter.
  4. The multifaceted roles of lysosomes in cancer.
  5. HRS dephosphorylation at membrane contact sites promotes sorting within multivesicular endosomes.
  6. Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis.
  1. Cell Commun Signal. 2026 Aug 08. pii: 596. [Epub ahead of print]24(1):
    Lysosomal alkalinization: a convergent mechanism in lysosomal storage disorders and classical neurodegenerative diseases.
    Ankur Rakesh Dubey, Saurabh Kumar, Ruchira Singh.
      Lysosomes are important cellular organelles involved in the recycling of biomolecules in the cell. The acidic intraluminal pH of the lysosome is necessary for the functioning of various hydrolytic enzymes involved in the recycling of biomolecules. Elevated lysosomal pH has been consistently documented in pathological conditions associated with progressive neurodegeneration, including several classical neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease) and lysosomal storage disorders or LSDs (e.g., Gaucher disease, CLN3 disease). This review focuses on the molecular mechanisms of lysosomal pH regulation, describing the critical roles of vacuolar ATPases and ion channels in maintaining lysosomal pH homeostasis. Further, we highlight how defective acidification of the lysosome can promote common cellular defects linked with both classical neurodegeneration and LSDs. The review also draws a parallel between the pathological consequences of experimentally-induced lysosomal alkalinization and two complex classes of disorders: classical neurodegeneration and LSDs. This comparison raises the possibility that lysosomal pH is one of the multiple shared contributing mechanisms for both conditions and, therefore, a conceivable therapeutic target of classical neurodegeneration and LSDs.
    Keywords:  Lysosomal acidification; Lysosomal alkalinization; Lysosome; Lysosome Storage Disorder; Neurodegeneration
    DOI:  https://doi.org/10.1186/s12964-026-03118-1
  2. EMBO J. 2026 Nov 02.
    Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.
    Izumi Yanatori, Tasuku Hirayama, Raku Son, Yasuhiro Murakawa, Yuta Matsuoka, Yuki Sugiura, Masato Niwa, Tatsuya Katsuno, Masahiko Tsujimoto, Hiroyuki Yasui, Atsuyasu Sato, Makoto Nakanishi, Kazuhiro Iwai.
      Iron accumulation is a conserved hallmark of cellular as well as organismal aging, yet its mechanistic role in senescence remains largely elusive. Here we show that the accumulation of ferrous iron (Fe2+) in lysosomes, a unique feature of senescent cells, is crucial for the induction of multiple senescence-associated phenotypes. Intriguingly, we found that this lysosomal Fe2+ sequestration is rendered "safe" by a dual metabolic adaptation that confers robust resistance to ferroptosis. First, Fe2+ accumulation triggers lysosomal alkalinization and subsequent cholesterol accumulation, which reinforces the lysosomal membrane against permeabilization. Second, senescent cells partition polyunsaturated fatty acids into lipid droplets, thereby depleting these ferroptosis-prone substrates from cellular membranes. Our findings establish that such cholesterol-enabled safe sequestration of Fe2+ serves as a central modulator linking senescence-associated remodeling to ferroptosis resistance. Modulating this lysosomal iron-centered pathway may provide new opportunities to target and control the behavior of senescent cells.
    DOI:  https://doi.org/10.1038/s44318-026-00939-1
  3. J Cell Sci. 2026 Nov 01. pii: jcs264858. [Epub ahead of print]139(21):
    Live-cell imaging of inter-organelle contacts using an integrated dimerization-dependent fluorescent protein reporter.
    Sophie Huver, Catherine Fromental-Ramain, Julie Eichler, Fleur Leroy, Céline Knorr, Corinne Wendling, Fabien Alpy, Catherine Tomasetto.
      Organelles communicate with each other by building membrane contact sites (MCSs) via specialized protein-protein and/or protein-membrane interactions. Conventional light microscopy cannot distinguish organelles connected by MCSs from those merely juxtaposed. In addition, organelle contacts are dynamic, yet only a limited number of tools are available to monitor MCSs in living cells. In this study, we developed a series of reporters based on dimerization-dependent fluorescent proteins (ddFP) to visualize, quantify and follow inter-organelle contacts. We first generated an integrated system specifically designed to study contacts between late endocytic compartments (late endosomes and lysosomes) and the endoplasmic reticulum (ER). This system utilizes a single plasmid coding for the two complementary ddFP components: green A (GA) and green B (GB) targeted to the ER and late endosomes and lysosomes (LE/Lys), respectively. This construct enabled the generation of a stable reporter cell line suitable for semi-quantitative imaging. The ddFP reporter, which we called ddFP LELYS-ER, did not perturb endogenous LE/Lys-ER contacts in stable cells, and detected changes in the number of LE/Lys-ER contacts, for example, upon downregulation of the ER-resident VAP tether protein family, or under conditions of lysosomal damage. Moreover, live-cell imaging revealed that LE/Lys-ER contacts have distinct shapes, mobilities and lifetimes. Finally, using the same vector design, we generated two additional integrated reporter systems adapted to the study of contacts between the ER and the plasma membrane, and between the ER and mitochondria.
    Keywords:  Dimerization-dependent fluorescent protein; Endoplasmic reticulum; Endosomes; Lysosomes; Membrane contact sites; Mitochondria; Organelles; Plasma membrane
    DOI:  https://doi.org/10.1242/jcs.264858
  4. Mol Oncol. 2026 Nov 04.
    The multifaceted roles of lysosomes in cancer.
    Jia Li, Kevin M Ryan.
      Cancer cells proliferate rapidly and require sustained supplies of nutrients and biosynthetic precursors. Lysosomes are more than terminal degradation sites: they recycle amino acids, sugars, lipids, nucleosides and ions, while also coordinating nutrient sensing, organelle communication and immune regulation. Consequently, lysosomal capacity can become selectively advantageous in tumours by linking nutrient salvage with growth control, organelle communication and inflammatory signalling. Enhanced lysosomal function can support tumour growth, invasion and therapy resistance. Here, we review four cancer-relevant dimensions of lysosomal capacity: catabolism and transport; mTORC1- and AMPK-linked nutrient sensing; membrane contact sites with the ER, mitochondria, and Golgi; and immune regulation spanning innate and adaptive responses and inflammatory control. These functions are context dependent: lysosomal quality control can restrain tumour initiation, whereas established cancers often exploit increased lysosomal capacity to support proliferation, invasion, metastasis and therapy resistance. Finally, we discuss lysosome-state biomarkers and lysosome-targeted strategies for patient stratification and rational combination therapy.
    Keywords:  cancer; lysosome; membrane contact sites; metabolism; nutrient sensing; tumour immunity
    DOI:  https://doi.org/10.1002/1878-0261.70349
  5. Cell Rep. 2026 Nov 03. pii: S2211-1247(26)01301-X. [Epub ahead of print]45(11): 118222
    HRS dephosphorylation at membrane contact sites promotes sorting within multivesicular endosomes.
    Minoo Razi, Louise H Wong, Douglas Grimes, Thomas Burgoyne, Pedro Fale, Ewan MacDonald, Emily R Eden, Michael J Clague, Sylvie Urbe, Clare E Futter.
      HRS is a receptor tyrosine kinase substrate and ESCRT machinery component. It enables sorting of ubiquitylated cargo into multivesicular endosomes (MVEs) for lysosomal degradation but also functions in receptor recycling. We show that co-depletion of its ESCRT-0 binding partners, STAM1 and STAM2, recapitulates defects in EGF receptor (EGFR) sorting onto intraluminal vesicles (ILVs) but does not mirror the increased MVE size evident after HRS depletion. Using mutagenesis of the endogenous gene or introduction of APEX2-tagged HRS variants, we find that HRS Y329/334 phosphorylation is dispensable for EGFR sorting and MVE size control. AnnexinA1 mediates ER:endosomal membrane contacts and promotes EGF-stimulated ILV formation. We show that reduced ILV formation on AnnexinA1 depletion is accompanied by increased HRS phosphorylation, likely through reduced HRS dephosphorylation by ER-localised PTP1B. Conversely, Y329/334 mutation renders ILV formation insensitive to AnnexinA1 depletion. Our data suggest that rapid HRS dephosphorylation at ER:MVE contacts promotes efficient ILV formation.
    Keywords:  AnnexinA1; CP: molecular biology; ESCRT; HRS phosphorylation; ILVs; MCS; MVE; endosomal sorting complex required for transport; intraluminal vesicles; membrane contact sites; multivesicular endosomes
    DOI:  https://doi.org/10.1016/j.celrep.2026.118222
  6. Cell. 2026 Nov 02. pii: S0092-8674(26)01139-6. [Epub ahead of print]
    Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis.
    Chisaka Kuehnemann, Samantha T Jezak, Bronwyn A Mogck, Niharika Kura, Rushmeen Tariq, Yuheng Che, Maija Vaittinen, Ioannis Siokas, Sharvari Deshpande, Carlyn Guthrie, Xuejuan Tan, Eliezer Aimontche, Aleksandra Aljakna Kahn, Peter Reifsnyder, Gung Lee, Amene Majidipur, Andrew H Kung, Qiaoling Wang, Diana Jurk, Tong Zheng, Andrew S Greenberg, Xiang-Dong Wang, Koji Kitazawa, Gregory Dolnikowski, Yong Cheng, Nirupa R Matthan, Arvind Ramanthan, Jennifer Lee, Daniel Roh, Howard H Chen, Jussi Pihlajamaki, Ron Korstanje, Christopher D Wiley.
      When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such responses are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here, we show that senescent cells increase import and membrane levels of multiple polyunsaturated fatty acids (PUFAs), but a specific intermediate PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3ω-6), is reduced. Exogenous repletion of DGLA instead results in cell death by ferroptosis. Senescent cells manifest additional features associated with ferroptosis, including labile iron and expression of lipoxygenases as well as low-level membrane peroxidation. Oral DGLA supplementation lowers markers of senescence in aged mice and improves age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates have lower markers of adipose tissue senescence. Together, our data implicate shifts in PUFA metabolism as a driver of decisions between senescence and ferroptosis.
    Keywords:  DGLA; PUFA; aging; desaturation; ferroptosis; lipid peroxidation; metabolism; obesity; senescence; senolytic
    DOI:  https://doi.org/10.1016/j.cell.2026.09.036
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