bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–12–07
five papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Molecular mechanisms of the lysosomal damage response and its roles in aging and disease.
  2. The transcription factor SKN-1 drives lysosomal enlargement during aging to maintain function.
  3. Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis.
  4. E3 ligase AREL1 controls perinuclear localization of lysosomes and supports Purkinje cell survival.
  5. ZIP14 upregulation leads to ferroptosis and lysosomal dysfunction through intracellular iron overload and induces myocardial ischemia/reperfusion injury in mouse hearts.
  1. J Cell Sci. 2025 Dec 01. pii: jcs264255. [Epub ahead of print]138(23):
    Molecular mechanisms of the lysosomal damage response and its roles in aging and disease.
    Shuhei Nakamura, Takayuki Shima, Tamotsu Yoshimori.
      Lysosomes are the main digestive organelles and serve as a signaling hub linking environmental cues to cellular metabolism. Through these functions, lysosomes play a crucial role in maintaining cellular and organismal homeostasis. However, how lysosomal homeostasis itself is maintained is not well understood. Lysosomes are frequently damaged by a variety of substances, including crystals, silica, lipids, bacteria, toxins, amyloid proteins and reactive oxygen species. When lysosomes are damaged, their acidic contents leak out, leading to oxidative stress, inflammation and cell death. Damaged lysosomes are thus harmful to cells, and to restore lysosomal function after damage, cells have developed several defense mechanisms, collectively called the lysosomal damage response (or endo-lysosomal damage response). Recent studies have shown that this response is composed of three main pathways depending on the degree and duration of damage - repair, removal of the damaged lysosomes, and lysosomal biogenesis and regeneration. Growing evidence suggest that the failure and/or dysregulation of this response is implicated in aging and several diseases, including neurodegenerative diseases and kidney disease. In light of the rapid growth of this field, this Review summarizes our current knowledge of the lysosomal damage response, its significance in aging and diseases, and future perspectives.
    Keywords:  Aging; Autophagy; Disease; Lysosomal damage; Lysosome
    DOI:  https://doi.org/10.1242/jcs.264255
  2. PLoS Biol. 2025 Dec 05. 23(12): e3003540
    The transcription factor SKN-1 drives lysosomal enlargement during aging to maintain function.
    Xinyu Wang, Huimin Liu, Xiaoman Wang, Ben Zhou, Haiqing Tang, Shanshan Pang.
      Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes. Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.
    DOI:  https://doi.org/10.1371/journal.pbio.3003540
  3. J Vis Exp. 2025 Nov 14.
    Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis.
    Katia S G Andrade, John Mably, Da-Zhi Wang, Zhigao Wang.
      Necroptosis, a form of regulated necrosis, culminates in cell membrane rupture. Our lab and others have discovered that lysosomal membrane permeabilization (LMP) is an early and crucial event in this process, preceding membrane rupture. Rapid LMP releases potent lysosomal enzymes, particularly proteases, into the cytosol, actively promoting cell death. Live-cell imaging provides an invaluable tool for detecting LMP during necroptosis in real-time. Several fluorescent dyes are highly effective: (1) pH-sensitive LysoTracker dyes track changes in lysosomal pH. A decrease in fluorescence signal indicates a loss of the lysosomal pH gradient, a primary sign of lysosomal dysfunction, which may be a precursor or direct consequence of LMP. (2) Fluorescein-labeled dextran beads are internalized and accumulate in lysosomes. Their release into the cytosol signals complete LMP and cargo leakage. Here, we observed a progressive loss of Lysotracker fluorescence, with diffusing Dextran fluorescence into the cytosol after necroptosis induction. Thus, the live-cell imaging methodology enables researchers to precisely track the timing and extent of lysosomal dysfunction, contributing to a more comprehensive understanding of necroptosis mechanisms and illuminating potential therapeutic interventions.
    DOI:  https://doi.org/10.3791/69495
  4. EMBO J. 2025 Dec 02.
    E3 ligase AREL1 controls perinuclear localization of lysosomes and supports Purkinje cell survival.
    Luyi Jiang, Jiangfen Tang, Ya-Fen Zhang, Wen-Xuan Zou, Gang Deng, Na Tian, Xiaolu Zhao, Lei Han, Kai Liu, Bao-Liang Song, Jie Luo.
      Localization of lysosomes influences their properties, e.g., perinuclear lysosomes are more acidic but less mobile compared with the peripheral ones. Furthermore, the endoplasmic reticulum (ER) can actively regulate the dynamics and functions of lysosomes via membrane contact sites. In this study, we find that ER-resident apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1) establishes membrane contacts with lysosomes by directly interacting with the Voa subunit of V-ATPase. AREL1 also catalyzes K33-linked polyubiquitylation of V-ATPase V1B2 subunit, inducing its binding to UBAC2 localized in the perinuclear ER. Depletion of AREL1 or UBAC2 increases the number of peripheral lysosomes that possess partially assembled V-ATPase, elevated luminal pH, and attenuated degradative capacity. Knockdown of ZRANB1, the deubiquitylating enzyme that antagonizes AREL1-mediated V1B2 ubiquitylation, promotes perinuclear clustering of lysosomes and increases lysosomal acidity and degradation. Mice lacking Arel1 exhibit age-dependent Purkinje cell loss, an ataxic phenotype, and motor impairment. Lipofuscin accumulation in the residual Purkinje cells of Arel1-/- mice indicates lysosomal dysfunction. Orchestration of lysosomal positioning and function by the AREL1-UBAC2-V-ATPase axis underscores the physiological significance of ER-regulated perinuclear lysosomal positioning in neurons.
    Keywords:  AREL1; Lysosomal Positioning; Purkinje Neurons; UBAC2; V-ATPase
    DOI:  https://doi.org/10.1038/s44318-025-00654-3
  5. J Mol Cell Cardiol. 2025 Nov 27. pii: S0022-2828(25)00219-6. [Epub ahead of print]
    ZIP14 upregulation leads to ferroptosis and lysosomal dysfunction through intracellular iron overload and induces myocardial ischemia/reperfusion injury in mouse hearts.
    Liang Zhao, Yuru Cao, Xianle Liu, Qing Yang, Zhelong Xu.
      While the ZIP family Zn2+ transporters such as ZIP2 and ZIP7 play critical roles in myocardial ischemia/reperfusion (I/R) injury by regulating Zn2+ homeostasis, little is known about the roles of the other ZIP family Zn2+ transporters in I/R injury. Here we report that ZIP14, a ZIP family Zn2+ transporter, contributes to the pathogenesis of myocardial I/R injury by controlling Fe2+ homeostasis. Mouse hearts were subjected to I/R in vivo. Lipid peroxides were measured with C11-BODIPY and MDA. Infarct size was measured with the TTC staining. The cardiac-specific ZIP14 knockdown (AAV-shZIP14) and overexpression (AAV-ZIP14) mice were generated by adopting the AAV system. AAV-shZIP14 decreased but AAV-ZIP14 increased Fe2+ levels in cardiomyocytes. ZIP14 is upregulated at reperfusion, and AAV-shZIP14 reduced but AAV-ZIP14 enhanced ferroptosis caused by I/R. ZIP14 upregulation led to lysosomal lipid peroxidation in a Fe2+-dependent manner, which ultimately contributes to myocardium injury by causing lysosomal membrane permeabilization (LMP) and impairment of autophagic flux. Our findings identify upregulation of ZIP14 leading to ferroptosis, LMP, and suppression of autophagic flux as a critical feature of myocardial I/R injury. Targeting cardiac ZIP14 upregulation may serve as a therapeutic strategy for the treatment of myocardial I/R injury.
    Keywords:  Autophagic flux; Ferroptosis; LMP; Myocardial I/R injury; ZIP14
    DOI:  https://doi.org/10.1016/j.yjmcc.2025.11.014
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