bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–10–11
eleven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells.
  2. Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.
  3. The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
  4. Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
  5. Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.
  6. Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes.
  7. Disrupted thyroid hormone-mitochondrial coupling in diabetic cardiomyopathy: a candidate upstream amplifier of metabolic and redox maladaptation.
  8. Gene therapy for rare lysosomal storage disorder nabs FDA approval.
  9. Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
  10. Diabetic cardiomyopathy as a disorder of proteostatic maladaptation: context-dependent ubiquitin-specific protease networks.
  11. One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.
  1. FEBS Lett. 2026 Oct 08.
    Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells.
    Na Yeon Park, Inho Kwon, Yong Hwan Kim, Ji-Eun Bae, Joon Bum Kim, Seong Hyun Kim, Sungho Maeng, Doo Sin Jo, Dong-Hyung Cho.
      Lysophagy selectively eliminates damaged lysosomes to preserve lysosomal homeostasis, but its regulatory mechanisms remain incompletely understood. Here, we identify dipeptidyl peptidase 7 (DPP7), a lysosomal serine protease, as a regulator of lysophagy. Inhibition or depletion of DPP7 impaired clearance of LLOMe-damaged lysosomes in HepG2 cells, as evidenced by sustained galectin-3 puncta and reduced lysophagic flux. DPP7 inhibition did not block TFEB activation; however, it markedly reduced ubiquitin accumulation on damaged lysosomes and attenuated the recruitment of SQSTM1 and LC3. This defect was accompanied by impaired lysosomal re-acidification and reduced maturation of cathepsin D and L. Together, our findings identify DPP7 as a novel modulator of ubiquitin-dependent lysophagy and reveal an unexpected role for a lysosomal peptidase in lysosomal quality control.
    Keywords:  DPP7; LLOMe; Lysophagy; Lysosomal integrity; UAMC00039
    DOI:  https://doi.org/10.1002/1873-3468.70482
  2. Mol Biol Cell. 2026 Oct 08. mbcE25090457
    Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.
    Shiraz Anwar, Solmaz Ebrahimi-Iranpour, Maria R Narciso, Jennifer Li, Saaimatul Huq, Tracy Lackraj, Tamara Beriia, Nazia Chowdhury, Mojca Mattiazzi Usaj, Roberto J Botelho.
      While lysosomes are typically globular in morphology, lipopolysaccharide-activated macrophages reorganize lysosomes into an expanded tubular network. Here, we sought to determine if the V-ATPase and the lysosomal pH contribute to LPS-mediated lysosome tubulation in macrophages. We found that inhibition of the V-ATPase prevented lysosome tubulation and collapsed preformed tubules. However, the V-ATPase also controls mTORC1 activity, which itself is needed for tubulation. To distinguish between lysosomal pH and mTORC1, we turned to NH4Cl, which alkalinized lysosomal pH but did not interfere with mTORC1; yet NH4Cl blocked tubulation showing that an acidic lysosomal pH is needed for lysosome remodelling. Moreover, clamping the pH to either acidic or alkaline pH caused tubules to collapse, indicating that the pH gradient promotes tubulation, rather than a specific pH. These effects were not due to altered microtubule organization or impaired lysosome motility, suggesting that motors remained associated with lysosomes. On the other hand, while LPS did not alter the average pH of spherical or tubular lysosomes, growing tubules displayed a more acidic peripheral end relative to the pericentral end. Based on this observation, we propose that a localized pH gradient along the tubule may enable tubulation by modulating factors that catalyse tubule growth. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-09-0457
  3. J Cell Biochem. 2026 Oct;127(10): e70133
    The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
    Xiao-Wen Zhang, Ming-Yue Wu, Qi Zhu, Xu Zhuang, Yu Dong, Shuang Zhang, Jia-Hong Lu.
      The vacuolar ATPase (V-ATPase) is essential for lysosomal acidification and autophagy, and its activity is regulated by nutrient-sensitive reversible assembly of its V1 and Vo domains. While mTORC1 is known to inhibit V-ATPase assembly, the precise molecular mechanisms remain incompletely understood. Here, using TurboID-based proximity labeling and quantitative mass spectrometry, we identified the R2TP complex subunits RPAP3 and PIH1D1 as novel autophagy-responsive interactors of the V-ATPase V1A subunit (encoded by ATP6V1A). We found that mTORC1 inhibition disrupts the R2TP-V1A interaction, promoting the relocation of the V1 domain to lysosomes and its assembly with the Vo domain to form active proton pumps. Functionally, knockdown of RPAP3 or PIH1D1 enhanced autophagic flux, increased lysosomal proteolytic activity, and promoted the clearance of soluble α-synuclein in a cellular model of Parkinson's disease (PD). Our study reveals the R2TP complex as a critical molecular switch that couples mTORC1 signaling to V-ATPase assembly and lysosomal function, thereby identifying a new pathway for regulating lysosomal catabolism with significant therapeutic potential for neurodegenerative disorders.
    Keywords:  R2TP complex; V‐ATPase; autophagy; lysosomal function; mTORC1
    DOI:  https://doi.org/10.1002/jcb.70133
  4. Nat Rev Mol Cell Biol. 2026 Oct 05.
    Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
    Susmita Kaushik, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA), the first-described selective lysosomal degradation pathway, is distinguished from other degradative pathways by the unique mechanism by which substrates reach the lysosomal lumen: CMA relies on a cytosolic targeting chaperone and a lysosomal membrane receptor that doubles as a translocation complex. In this Review, we highlight recent discoveries of additional molecular components involved in CMA and describe how genetic and pharmacological modulation of CMA in vivo, along with the identification of the subproteome degraded by CMA in different organs, has revealed an expanding range of physiological functions regulated by CMA in an organ-specific manner. CMA not only degrades damaged proteins but also targets fully functional proteins to terminate their physiological roles. Consequently, CMA dysfunction, as observed in ageing and age-related diseases, leads to cellular alterations beyond the mere accumulation of damaged proteins. We summarize recent findings linking CMA to common diseases and discuss efforts to therapeutically target CMA in these conditions.
    DOI:  https://doi.org/10.1038/s41580-026-01023-6
  5. Front Chem. 2026 ;14 1891677
    Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.
    Tengfei Zhao, Hanxu Huang, Yifan Wang, Yuliang Zhong, Zhiwei Zhong, Deting Xue, Wei Zhu, Kan Xu.
      Lysosomes are degradative, metabolic and signaling organelles in central nervous system (CNS) cells and play essential roles in neural homeostasis, injury responses and disease progression. Changes in lysosomal function are required for neurons, microglia, astrocytes and oligodendrocyte-lineage cells to adapt to proteotoxic stress, lipid overload, mitochondrial damage and inflammatory stimulation. Therefore, lysosomal activity in the CNS is regulated by diverse chemical and cellular cues, including luminal acidification, hydrolase maturation, ion transport, membrane integrity, lipid handling and transcriptional lysosome biogenesis. Here, we summarize current knowledge of lysosomal organization and function in neural cells, including lysosomal membrane signaling, vacuolar H+-ATPase (V-ATPase)-dependent acidification, ion and redox regulation, lysosomal membrane quality control, and metabolic recycling of proteins, lipids, glycans and damaged organelles. We then survey pathological lysosomal remodeling in spinal cord injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease and related neurological disorders. Across these conditions, lysosomal remodeling may initially support cargo clearance and stress adaptation, but becomes maladaptive when degradative capacity, membrane repair or lipid-processing ability fails to meet cellular demand. Finally, we discuss lysosome-oriented therapeutic strategies for neural repair, including restoration of lysosomal acidification and hydrolase activity, transcription factor EB/transcription factor E3 (TFEB/TFE3)-mediated lysosomal biogenesis, regulation of lysosomal ion channels, enhancement of myelin lipid turnover, and lysosome-responsive nanomedicine. This Review highlights lysosomes as active organizers of CNS injury and repair rather than passive endpoints of degradation.
    Keywords:  central nervous system; lysosome; metabolism; neural repair; neuroinflammation
    DOI:  https://doi.org/10.3389/fchem.2026.1891677
  6. Nat Commun. 2026 09 03. pii: 10512. [Epub ahead of print]17(1):
    Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes.
    Dávid Hargitai, Márton Molnár, András Rubics, Iván Bodor, Dóra Baukál, Anikó Nagy, Virág Balogh, Zsófia Simon-Vecsei, Gábor Juhász, Péter Lőrincz.
      Endosomal maturation determines whether internalized cargo is recycled or degraded, yet the logic governing early endosomal fusion remains incompletely defined. Although commonly depicted as a linear Rab5-to-Rab7 transition mediated by a single SNARE pathway, we show that early endosome maturation is driven by multiple parallel, non-interchangeable SNARE complexes. Using Drosophila nephrocytes as a tractable in vivo model, we define a Syx12L-Snap29-Ykt6 complex that mediates homotypic early endosomal fusion and identify two related assemblies-Syx7L-Snap29-Ykt6 and Syx7L-Snap29-Vamp7-that promote later endosomal and lysosomal fusion with distinct Rab requirements. When the canonical Syx12L pathway is disrupted, alternative complexes remain active and generate aberrant endolysosomal swirls which also form in the absence of Rab5 or early endosomal tethers. Thus, Rab5-independent membrane progression toward lysosomes persists but is insufficient to produce fully functional degradative organelles. Together, our findings reveal a network of parallel fusion pathways underlying endosome maturation.
    DOI:  https://doi.org/10.1038/s41467-026-77479-z
  7. Front Endocrinol (Lausanne). 2026 ;17 1987603
    Disrupted thyroid hormone-mitochondrial coupling in diabetic cardiomyopathy: a candidate upstream amplifier of metabolic and redox maladaptation.
    Yebin Xia, Wenjie Zhang, Jinjian Guo.
      Diabetic cardiomyopathy (DCM) is characterized by mitochondrial metabolic inflexibility, redox imbalance and defective organelle quality control, yet the endocrine program coordinating these abnormalities remains incompletely defined. Thyroid hormone (TH) is a major regulator of cardiac energy metabolism and mitochondrial adaptation. In experimental diabetes, myocardial triiodothyronine (T3) can decline despite preserved circulating thyroid hormone concentrations, accompanied by type 3 iodothyronine deiodinase (DIO3) induction and altered TH transport. We propose that this local defect disrupts thyroid hormone-mitochondrial coupling and may thereby constrain adaptation of substrate oxidation, oxidative phosphorylation, redox defense and organelle turnover. Preclinical diabetic-heart studies demonstrate local TH dysregulation and show that appropriately dosed T3 treatment can reverse selected structural and functional abnormalities. Complementary cardiac studies identify mitochondrial biogenesis, reactive oxygen species control, mitophagy and calcium handling as plausible downstream effectors. Together, these findings support impaired local TH signaling as an underrecognized candidate upstream mechanism linking the diabetic endocrine environment to mitochondrial maladaptation. A tissue-specific therapeutic-window model may reconcile the adverse consequences of both deficient and excessive TH signaling while providing a framework for biomarker development, mechanistic testing and precision intervention in DCM.
    Keywords:  DIO3; diabetic cardiomyopathy; metabolic flexibility; mitochondria; mitochondrial quality control; redox signaling; thyroid hormone
    DOI:  https://doi.org/10.3389/fendo.2026.1987603
  8. Nat Rev Drug Discov. 2026 Oct 05.
    Gene therapy for rare lysosomal storage disorder nabs FDA approval.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-026-00160-z
  9. Science. 2026 Oct 08. 394(6820): eadx9628
    Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
    Sho Aki, Mayuko Segawa, Vincent Anton, Suvagata R Chowdhury, Shun Nagashima, Isshin Shiiba, Dane M Wolf, Ikuko Koyama-Honda, Ayumu Sugiura, Joe Ganellin, Mark Johnson, Sakie Katsumura, Maki Sugaya, Yasunori Fujita, Koki Nakamura, Kazuaki Yoshioka, Hisamichi Naito, Yoh Takuwa, Ikuroh Ohsawa, Yusuke Hirabayashi, Shigeru Yanagi, Masahiro Morita, Tsuyoshi Osawa, Julien Prudent.
      Mitochondria are dynamic organelles that remodel their shape to regulate cell fate. Mitochondrial division involves interactions with the endoplasmic reticulum (ER), lysosomes, and trans-Golgi network-derived vesicles to facilitate membrane scission. How interorganelle contacts regulate mitochondrial membrane fusion remains largely unknown. Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites. Accordingly, loss of class II PI3-kinase isoforms α and β (PI3K-C2α and PI3K-C2β), which generate PI(3,4)P2, led to mitochondrial fragmentation resulting from impaired fusion. Furthermore, cardiomyocyte-specific PI3K-C2α and PI3K-C2β double-deletion mice exhibited mitochondrial fragmentation and heart failure. Thus, subpopulations of Golgi-derived vesicles carrying different phosphoinositides control mitochondrial membrane remodeling and homeostasis.
    DOI:  https://doi.org/10.1126/science.adx9628
  10. Front Cell Dev Biol. 2026 ;14 1910665
    Diabetic cardiomyopathy as a disorder of proteostatic maladaptation: context-dependent ubiquitin-specific protease networks.
    Xiangyun Meng, Shuming Guo, Hui Lin, Ruchao Li, Wei Peng, Lingang Sun, Xiaowei Shi, Lixia Yang.
      Diabetic cardiomyopathy (DCM) is a multidimensional myocardial remodeling disorder driven by interconnected metabolic, inflammatory, ferroptotic, autophagic and fibrotic programs, yet the post-translational mechanisms that convert diabetic stress into persistent injury remain incompletely integrated. Ubiquitin-specific proteases (USPs) regulate substrate stability, ubiquitin-chain architecture and signaling-complex dynamics and therefore represent an important proteostatic layer in DCM. Rather than assigning fixed protective or maladaptive identities to individual enzymes, this review organizes current evidence according to specific USP-substrate axes and their cellular and disease contexts. Predominantly protective axes include USP28-PPARα/Mfn2, USP8-Parkin, USP13-NLRP3, USP20-p62/STING, USP18-dependent stabilization of Notch1 or FOXC2, and the endothelial USP33-ATG7/FIS1 pathway. Predominantly injurious axes include USP38-ACAD11, USP14-VDAC1 and USP24-associated ferroptotic and autophagy-disruptive signaling. USP7 exemplifies substrate-dependent bidirectionality: USP7-PGC1β promotes metabolic dysfunction, whereas USP7-NRF2 supports GPX4-dependent ferroptosis resistance during empagliflozin treatment. By integrating these axes across pathological modules and cardiac cell types, this review reframes DCM as a disorder of context-dependent proteostatic maladaptation and highlights substrate-resolved USP regulation as a priority for future mechanistic and translational investigation.
    Keywords:  autophagy; deubiquitination; diabetic cardiomyopathy; ferroptosis; mitochondrial dysfunction; ubiquitin-specific protease
    DOI:  https://doi.org/10.3389/fcell.2026.1910665
  11. Front Neurosci. 2026 ;20 1941231
    One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.
    Robert C C Mercer.
      Protein misfolding neurodegenerative diseases are invariably fatal conditions with a paucity of available and universally embraced disease modifying therapies. It is crucial, therefore, to identify additional potential candidate molecules and/or targets with which to work toward human trials. In this mini-review, I will highlight the recent discoveries of compounds that physically associate with the lysosome to enhance or restore its activity. One potential target for the development of additional therapeutics that emerges from the consideration of these molecules is the proton pump responsible for acidification of the lysosomal lumen, the vacuolar H+-ATPase. While the approach of directly targeting lysosomal activity remains experimental at present, the wealth of evidence pointing to the involvement of the endolysosomal-autophagic system across protein misfolding neurodegenerative diseases raises the tantalizing possibility that this therapeutic modality could have broad applicability.
    Keywords:  Aβ; TDP-43; lysosome; neurodegeneration; prion; tau; therapeutics; α-synuclein
    DOI:  https://doi.org/10.3389/fnins.2026.1941231
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