bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–11–30
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
  2. Loss of ARF5 impairs recovery after lysosomal damage.
  3. Homocysteine disrupts lysosomal function by V-ATPase inhibition.
  4. Portioning organelles for autophagic clearance.
  5. Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells.
  6. Autophagy and GLUT1 Trafficking: An Overview of Molecular Mechanisms.
  7. Ferroptosis in the pathogenesis of diabetic cardiomyopathy: mechanisms and therapeutic potential.
  1. Nat Commun. 2025 Nov 28. 16(1): 10761
    Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
    Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.
      Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-65798-6
  2. Front Mol Biosci. 2025 ;12 1699266
    Loss of ARF5 impairs recovery after lysosomal damage.
    Martyna O Iwaniec, Christopher J Bott, James E Casanova.
      Lysosomal dysfunction is a defining feature of aging and neurodegenerative diseases, where lysosomal membrane permeabilization and release of its contents can trigger cellular death pathways. To counteract this, cells rely on lysosomal quality control mechanisms, many of which depend on lipid delivery to repair damaged membranes. However, the regulatory pathways governing this process remain unclear. In this study, we investigated whether canonical ARF GTPases, best known for their roles in Golgi and endosomal vesicular trafficking, are recruited to damaged lysosomes and contribute to their repair. Using LysoIP-based lysosome isolation, super-resolution immunofluorescence imaging, and functional assays in HeLa and HEK293 cells, we found that ARF1, ARF5, and ARF6 localize to lysosomal membranes following L-leucyl-L-leucine methyl ester (LLOME)-induced permeabilization. While loss of ARF6 did not impair recovery, ARF5 depletion resulted in a nearly complete block of lysosomal repair. These findings identify ARF proteins as early responders to lysosomal damage and suggest isoform-specific roles in coordinating the pathways of lysosomal quality control.
    Keywords:  ARF; ORP; OSBP; lysosome; repair
    DOI:  https://doi.org/10.3389/fmolb.2025.1699266
  3. J Cell Biol. 2026 Jan 05. pii: e202503081. [Epub ahead of print]225(1):
    Homocysteine disrupts lysosomal function by V-ATPase inhibition.
    Yang Yang, Qianjin Kong, Chaolian Liu, Fengyang Wang, Meijiao Li, Shalan Li, Yuehui Shi, Leonard Krall, Xin Wang, Shan He, Kai Jiang, Xuna Wu, Mei Yang, Chonglin Yang.
      Lysosomes are degradation and signaling organelles central to metabolic homeostasis. It remains unclear whether and how harmful metabolites compromise lysosome function in the etiopathology of metabolic disorders. Combining Caenorhabditiselegans and mouse models, we demonstrate that homocysteine, an intermediate in methionine-cysteine metabolism and the cause of the life-threatening disease homocystinuria, disrupts lysosomal functions. In C. elegans, mutations in cystathionine β-synthase cause strong buildup of homocysteine and developmental arrest. We reveal that homocysteine binds to and homocysteinylates V-ATPase, causing its inhibition and consequently impairment of lysosomal degradative capacity. This leads to enormous enlargement of lysosomes with extensive cargo accumulation and lysosomal membrane damage in severe cases. Cbs-deficient mice similarly accumulate homocysteine, displaying abnormal or damaged lysosomes reminiscent of lysosomal storage diseases in multiple tissues. These findings not only uncover how a metabolite can damage lysosomes but also establish lysosomal impairment as a critical contributing factor to homocystinuria and homocysteine-related diseases.
    DOI:  https://doi.org/10.1083/jcb.202503081
  4. Autophagy. 2025 Nov 28.
    Portioning organelles for autophagic clearance.
    Mikhail Rudinskiy, Maurizio Molinari.
      The lysosomal/vacuolar clearance of portions of organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus and the nucleus, organellophagy, is mediated by autophagy receptors anchored at the surface of their respective organelles. Organellophagy receptors are activated, induced or derepressed in response to stimuli such as nutrient or oxygen deprivation, accumulation of toxic or aged macromolecules, membrane depolarization, pathogen invasion, cell differentiation and many others. Their activation drives the portioning of the homing organelle, and the engagement of Atg8/LC3/GABARAP (LC3) proteins via LC3-interacting regions (LIRs) that results in autophagic clearance. In our latest work, we elaborate on the fact that all known mammalian and yeast organellophagy receptors expose their LIR embedded within intrinsically disordered regions (IDRs), i.e. cytoplasmic stretches of amino acids lacking a fixed three-dimensional structure. Our experiments reveal that the IDR modules of organellophagy receptors are interchangeable, required and sufficient to induce the fragmentation of the organelle that displays them at the limiting membrane, independent of LC3 engagement. LC3 engagement drives lysosomal delivery. Building on these findings, we propose harnessing practical and therapeutic potential of controlled organelle fragmentation and organellophagy through ORGAnelle TArgeting Chimeras (ORGATACs).
    Keywords:  Endoplasmic reticulum (Er)phagy; ORGAnelle TArgeted chimeras (ORGATACs); intrinsically disordered regions (IDRs); mitophagy; organellophagy receptors; targeted organelle degradation
    DOI:  https://doi.org/10.1080/15548627.2025.2597458
  5. Cell Stem Cell. 2025 Nov 24. pii: S1934-5909(25)00405-9. [Epub ahead of print]
    Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells.
    Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G Beaumont, Deanna L Benson, Nikolaos Tzavaras, Mickaël M Ménager, Saghi Ghaffari.
      Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging-beyond their passive mediation of autophagy-is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.
    Keywords:  MMP; aging; cGas-STING; hematopoietic stem cell; inflammation; interferon; lysosomes; mitochondria; mtDNA; quiescence
    DOI:  https://doi.org/10.1016/j.stem.2025.10.012
  6. Am J Physiol Cell Physiol. 2025 Nov 27.
    Autophagy and GLUT1 Trafficking: An Overview of Molecular Mechanisms.
    Sara Petrosino, Paolo Grumati.
      Autophagy is a catabolic process that enables cellular metabolic adaptation in response to nutrient deprivation. It facilitates the degradation of proteins and cellular components within lysosomes to generate essential metabolites. The glucose transporter 1 (GLUT1) is among the proteins that can undergo autophagy-mediated degradation in response to metabolic stimuli. GLUT1 is essential for cellular glucose supply in several tissues. Notably, GLUT1 facilitates glucose transport across the blood-brain barrier, creating a concentration gradient from the bloodstream into the brain's interstitial fluid. The presence of GLUT1, at the plasma membrane, is the first step in initiating glucose uptake and driving glycolysis inside the cell. Glycolysis can be initiated in response to several stimuli, including glucose availability, autophagy inhibition and growth factor accessibility. In this review, we highlight recently described mechanisms that govern the subcellular distribution of GLUT1 with a focus on autophagy-mediated trafficking. Understanding how autophagy coordinates GLUT1 sorting in response to metabolic demands may uncover novel therapeutic targets for metabolic disorders characterized by dysregulated GLUT1 trafficking.
    Keywords:  Autophagy; GLUT1; Metabolism; Signalling; Trafficking
    DOI:  https://doi.org/10.1152/ajpcell.00551.2025
  7. Cardiovasc Diabetol. 2025 Nov 26. 24(1): 449
    Ferroptosis in the pathogenesis of diabetic cardiomyopathy: mechanisms and therapeutic potential.
    Qingqing Zhao, Ming Wang, Ning Zhou, Yan Wang.
      Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus, often leading to heart failure and increased mortality. While its pathogenesis remains incompletely understood, key contributors include chronic hyperglycemia, hyperlipidemia, insulin resistance, myocardial fibrosis, oxidative stress, mitochondrial dysfunction, and aberrant cell death pathways. Emerging evidence highlights ferroptosis, an iron-dependent form of regulated cell death, as a critical player in DCM progression. This review synthesizes current knowledge on the mechanistic links between ferroptosis and DCM, focusing on endothelial dysfunction, myocardial fibrosis, oxidative stress, and mitochondrial damage. We also discuss promising therapeutic strategies targeting ferroptosis to alleviate DCM, including pharmacological inhibitors, natural compounds, and non-coding RNAs, while identifying gaps for future research.
    Keywords:  Diabetic cardiomyopathy; Ferroptosis; Mitochondrial dysfunction; Oxidative stress; Therapeutic targets
    DOI:  https://doi.org/10.1186/s12933-025-03001-2
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒01 at 16:15.