bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–03–22
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
  2. Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
  3. Mitochondria acidify lysosomes through membrane contacts.
  4. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  5. Inflammatory signalling in diabetic cardiomyopathy: molecular mechanisms and potential therapeutic strategies.
  6. Organelle homeostasis disruption: A driving force in the progression of cardiomyopathy (Review).
  7. Visualizing suborganellar lipid distribution using correlative light and electron microscopy.
  1. Nat Commun. 2026 03 14. pii: 2487. [Epub ahead of print]17(1):
    Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
    Valentin Duhay, Miaomiao Tian, Klaudia Kosieradzka, Michael Ebner, Wen-Ting Lo, Michael Krauss, Henner-Linus Sprengel, Matthias Voss, Mara Riechmann, Jeffrey N Savas, Michael Schwake, Volker Haucke, Markus Damme.
      Lysosomes are highly dynamic organelles that serve antagonistic functions as terminal catabolic stations for the degradation of macromolecules and as central metabolic decision centers for anabolic growth signaling. Lysosome dysfunction is implicated in various human diseases. The physiological roles of lysosomes are linked to the control of lysosome position and dynamics via the activity of the kinesin-activating small GTPase ARL8. How the activity of ARL8 is regulated remains poorly understood. Here, we identify the GTPase-activating Tre-2/Bub2/Cdc16 (TBC) domain protein TBC1D9B as a critical negative regulator of ARL8B function. We demonstrate that TBC1D9B is associated with the lysosomal membrane protein TMEM55B, directly binds to ARL8B-GTP, and stimulates its GTPase activity. Knockout of TBC1D9B or its binding partner TMEM55B causes lysosome dispersion, defective autophagic flux, and impairs the adaptive degradative response of cells to limiting nutrient supply. These lysosomal phenotypes of TBC1D9B loss are occluded by concomitant depletion of ARL8 in cells. Collectively, our data unravel a key role for TBC1D9B in controlling lysosome function by serving as a negative regulator of ARL8 activity.
    DOI:  https://doi.org/10.1038/s41467-026-70345-y
  2. Nat Metab. 2026 Mar 18.
    Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
    Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.
      Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.
    DOI:  https://doi.org/10.1038/s42255-026-01484-1
  3. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00190-7. [Epub ahead of print]45(3): 117112
    Mitochondria acidify lysosomes through membrane contacts.
    Zhiqi Tian, Rui Chen, Guiqian Fang, Kangqiang Qiu, Weijun Wu, Xintian Shao, Daili Liu, Huilin Que, Xueqian Wang, Ji Gao, Jianyu Zhang, Bidyut Kundu, Qixin Chen, Jun-Lin Guan, Yueguang Rong, Ben Zhong Tang, Kai Li, Yujie Sun, Jiajie Diao.
      The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.
    Keywords:  CP: cell biology; lysosome acidification; mitochondria-lysosome contact; proton flux
    DOI:  https://doi.org/10.1016/j.celrep.2026.117112
  4. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  5. Nat Rev Cardiol. 2026 Mar 20.
    Inflammatory signalling in diabetic cardiomyopathy: molecular mechanisms and potential therapeutic strategies.
    Miles J De Blasio, Rebecca H Ritchie.
      Diabetes mellitus and the associated increased risk of cardiovascular disease is a major health-care issue worldwide. Diabetic cardiomyopathy, a complication of diabetes mellitus, is driven primarily by hyperglycaemia and hyperlipidaemia, which promote cardiac oxidative stress, mitochondrial dysfunction and pathological cardiac remodelling, leading to impaired cardiac function and eventual heart failure. Over the past 30 years, research on diabetic cardiomyopathy and other diabetes-associated cardiovascular diseases has focused on the role of chronic inflammation. Inflammation is a complex process involving pro-inflammatory cytokines, chemokines, activation of resident immune cells, and recruitment of immune cells to sites of injury, processes that are exacerbated in the setting of diabetes. Evidence now suggests that the inflammatory processes caused by persistent hyperglycaemia and hyperlipidaemia in diabetes contribute to the impairment of cardiac function. Importantly, no treatment options are available to reverse diabetic cardiomyopathy, with clinicians relying on strategies to delay or halt the progression of the disease. In this Review, we describe the inflammatory signalling pathways involved in diabetic cardiomyopathy and discuss strategies that can potentially be used to target these inflammatory pathways for the treatment of diabetic cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41569-026-01274-y
  6. Exp Ther Med. 2026 May;31(5): 118
    Organelle homeostasis disruption: A driving force in the progression of cardiomyopathy (Review).
    Yuxing Hou, Chao Li, Youyou Chen, Danfeng Zhong, Miaomiao Chai, Lijiao Mo, Senna Lin, Fangfang Huang, Qi Chen.
      Cardiomyopathy is a complex heart disease with structural and functional defects of the myocardium, often leading to poor clinical outcomes. While traditional research has focused on myofibrillar pathology and ion channel dysfunction, emerging evidence indicates that organelle homeostasis serves a central role in the pathogenesis of the disease. Mitochondrial dysfunction disrupts energy metabolism, calcium handling, dynamics and mitophagy. Golgi fragmentation, impaired glycosylation and abnormal vesicular trafficking jeopardize protein maturation and secretion. Endoplasmic reticulum stress causes myocardial injury via unfolded protein response, calcium dyshomeostasis and disruptions of lipid metabolism. Lysosomal degradation is disrupted by autophagic dysfunction, enzyme dysregulation and calcium signaling abnormalities. Ribosomes regulate proteostasis by defective biogenesis, quality control and translational dysregulation. Nuclear envelope instability and intercalated disc dysfunction disrupt normal mechanical and gene regulation in the development of cardiomyopathy. In combination, these findings support the concept of cardiomyopathy as a multi-organelle network disease driven by coordinated dysfunction of interconnected organelles. This review systematically summarizes current evidence on organelle-specific and inter-organelle mechanisms underlying cardiomyopathy, highlighting how disrupted organelle homeostasis collectively contributes to disease initiation and progression.
    Keywords:  Golgi apparatus; cardiomyopathy; endoplasmic reticulum; intercalated disc; lysosome; mitochondria; organelle homeostasis; ribosome
    DOI:  https://doi.org/10.3892/etm.2026.13113
  7. Nat Cell Biol. 2026 Mar 20.
    Visualizing suborganellar lipid distribution using correlative light and electron microscopy.
    H Mathilda Lennartz, Suman Khan, Weihua Leng, Kristin Böhlig, Gunar Fabig, Yannick Kieswald, Falk Elsner, Nadav Scher, Michaela Wilsch-Bräuninger, Ori Avinoam, André Nadler.
      Lipids and proteins compartmentalize biological membranes into nanoscale domains, which are crucial for signalling, intracellular trafficking and many other cellular processes. Studying nanodomain function requires the ability to measure protein and lipid localization at the nanoscale. Current methods for visualizing lipid localization do not meet this requirement. Here we introduce a correlative light and electron microscopy workflow to image lipids (Lipid-CLEM), combining near-native lipid probes and on-section labelling by click chemistry. This approach enables the quantification of relative lipid densities in membrane nanodomains. We find differential partitioning of sphingomyelin into intraluminal vesicles, recycling tubules and the boundary membrane of the early endosome, representing a degree of nanoscale organization previously observed only for proteins. We anticipate that our Lipid-CLEM workflow will greatly facilitate the mechanistic analysis of lipid functions in cell biology, allowing for the simultaneous investigation of proteins and lipids during membrane nanodomain assembly and function.
    DOI:  https://doi.org/10.1038/s41556-026-01915-x
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