bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–10–05
five papers selected by
Satoru Kobayashi, New York Institute of Technology



  1. PLoS Biol. 2025 Sep 30. 23(9): e3002957
      Lysosomes are essential for neuronal homeostasis, providing degradation and recycling functions necessary to support neurons' complex operations and long lifespans. However, the regulation of lysosomal degradative capacity in healthy neurons is poorly understood. Here, we investigate the role of HLH-30, the sole Caenorhabditis elegans homolog of Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy that is thought to predominantly function in the context of starvation or stress. We demonstrate that HLH-30 is dispensable for neuronal development but acts cell-intrinsically to expand lysosomal degradative capacity during early adulthood. Loss of HLH-30 leads to lysosomal dysfunction and delayed turnover of synaptic vesicle proteins from the synapse. Notably, we show that basal HLH-30 activity is sufficient to expand neuronal lysosomal capacity without nuclear enrichment, in contrast to the nuclear translocation associated with starvation- and stress-induced activation of TFEB and HLH-30. Furthermore, we show that neuronal lysosomal function declines with age in wild-type animals, and this corresponds to a decrease in basal HLH-30-mediated transcription. We further demonstrate that basal HLH-30 activity is crucial for neuron maintenance: lysosomal dysfunction due to inadequate HLH-30 activity leads to dendrite degeneration and aberrant outgrowths. In summary, our study establishes a critical role for HLH-30/TFEB in promoting lysosomal capacity to preserve neuronal homeostasis and structural integrity of mature neurons in vivo.
    DOI:  https://doi.org/10.1371/journal.pbio.3002957
  2. J Mater Chem B. 2025 Sep 29.
      Lysosomal pH is a crucial intracellular parameter for evaluating cellular metabolism, as even minor fluctuations are closely associated with various physiological disorders. Ratiometric fluorescent probes have been developed for monitoring lysosomal pH changes through molecular imaging. However, most of the reported probes suffer from limitations such as inadequate intracellular calibration and short excitation and emission wavelengths, which hinder their accurate pH quantification and restrict their applicability in vivo. Here we report a ratiometric fluorescent probe HeCypH, which was synthesized via a simple approach, to track pH fluctuations. The probe design relies on a hemicyanine scaffold fused with an intramolecular oxazinane ring, which undergoes a pH-responsive ring-opening process. Under acidic conditions, the open-ring form HeCypH-O exhibits two red/near-infrared emission peaks at 615 nm and 722 nm. Confocal fluorescence imaging in living cells revealed that HeCypH selectively localizes in lysosomes and enables ratiometric measurement of intracellular pH with high precision. Moreover, the excellent pH sensitivity, reversibility, and red-shifted emissions of HeCypH make it well suited for real-time monitoring of pH fluctuations and deep-tissue bioimaging in a mouse model.
    DOI:  https://doi.org/10.1039/d5tb01801c
  3. Nat Cardiovasc Res. 2025 Sep 29.
      Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood, and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phagolysosome. Here we show that glycogen receptor protein starch binding domain protein 1 (STBD1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo, and that deficiency of a specific ATG8 family protein, γ-aminobutyric acid type A receptor-associated protein-like 1 (GABARAPL1), is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and the diastolic performance of 'diabetic' human induced pluripotent stem cell-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease.
    DOI:  https://doi.org/10.1038/s44161-025-00726-x
  4. Exp Gerontol. 2025 Oct 01. pii: S0531-5565(25)00242-6. [Epub ahead of print] 112913
      Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.
    Keywords:  Cellular senescence; Mitochondrial dysfunction; Molecular mechanism; Organelle
    DOI:  https://doi.org/10.1016/j.exger.2025.112913