bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–11–16
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Sphinganine-induced lysosomal membrane permeabilization: Interplay with subcellular oxidative levels.
  2. Palmitate impairs autophagic degradation via oxidative stress-perilysosomal Ca2+ overload-mTORC1 activation in pancreatic β-cells.
  3. DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
  4. Sphingolipid and methionine metabolism in aging.
  5. Ceramide as a Biomarker for HFpEF in Women: Menopause, Aging, and Pregnancy.
  6. Autophagosome marker, LC3, is released extracellularly via several distinct pathways.
  1. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Nov 08. pii: S1388-1981(25)00113-1. [Epub ahead of print]1871(1): 159705
    Sphinganine-induced lysosomal membrane permeabilization: Interplay with subcellular oxidative levels.
    Guodong Cheng, Changxi Qi, Huiling Xu, Xiaozhou Wang, Muzi Li, Huahua Chen, Pimiao Zheng, Yongxia Liu, Jianzhu Liu, Xiaona Zhao.
      Sphinganine (SA), a fundamental sphingolipid whose cytotoxicity remains incompletely characterized, has received less attention compared to other sphingoid bases. Here, we demonstrate that SA predominantly triggers cell death via lysosomal membrane permeabilization (LMP) resulting from pH dysregulation and osmotic imbalance, rather than through direct ROS-mediated mechanisms, although mitochondrial ROS contribute to oxidative stress. SA-induced mitochondrial fragmentation significantly increased hydrogen peroxide levels in both the mitochondrial matrix and intermembrane space (IMS). Strikingly, lysosomes exhibited spatial colocalization with elevated hydrogen peroxide microdomains under SA exposure, suggesting a redox-dependent mechanism governing organelle repositioning. The cysteine protease inhibitor E64D attenuated SA-induced apoptosis through suppressing cathepsin B/L release, confirming lysosomal membrane permeabilization as an executor of apoptotic signaling. These findings unveil SA's dual-targeting organelle toxicity mechanism. Our study not only elucidates key aspects of sphingolipid-mediated cytotoxicity but also provides therapeutic rationale for counteracting fumonisin B1 (FB1)-induced pathologies and related sphingolipid disorders, potentially through lysosomal stabilization or targeted ROS modulation.
    Keywords:  Lysosomal membrane permeabilization; Sphinganine; Subcellular oxidative levels
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159705
  2. JCI Insight. 2025 Nov 11. pii: e192827. [Epub ahead of print]
    Palmitate impairs autophagic degradation via oxidative stress-perilysosomal Ca2+ overload-mTORC1 activation in pancreatic β-cells.
    Ha Thu Nguyen, Luong Dai Ly, Thuy Thi Thanh Ngo, Soo Kyung Lee, Carlos Noriega Polo, Subo Lee, Taesic Lee, Seung-Kuy Cha, Xaviera Riani Yasasilka, Kae Won Cho, Myung-Shik Lee, Andreas Wiederkehr, Claes B Wollheim, Kyu-Sang Park.
      Saturated fatty acids impose lipotoxic stress on pancreatic β-cells, leading to β-cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and β-cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTORC1 activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in β-cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by an mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca2+ overload, strategies such as lowering extracellular Ca2+, employing voltage-gated Ca2+ channel blocker or ATP-sensitive K+ channel opener effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca2+ into the endoplasmic reticulum (ER) with an ER Ca2+ ATPase activator, restores TRPML1 activity, promotes autophagic flux, and improves survival of β-cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress-Ca2+ overload-mTORC1 pathway involvement in TRPML1 suppression and defective autophagy during β-cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.
    Keywords:  Aging; Autophagy; Calcium signaling; Diabetes; Endocrinology
    DOI:  https://doi.org/10.1172/jci.insight.192827
  3. Nat Commun. 2025 Nov 10. 16(1): 9878
    DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
    Cristian Ricaurte-Perez, Joshua P Gill, P Kerr Wall, Olga Dubuisson, Kathryn R DeLeo, K Adam Bohnert, Alyssa E Johnson.
      Transcription factors DAF-16/FOXO and HLH-30/TFEB have been linked to aging regulation, but how they synergize to promote longevity is not fully understood. Here, we reveal a functional interaction between these two transcription factors that supports healthier aging in Caenorhabditis elegans. Namely, DAF-16 and HLH-30 cooperate to trigger robust lysosomal tubulation under various contexts, which contributes to systemic health benefits in late age. Remarkably, lysosome tubulation can be artificially induced via overexpression of a small lysosomal gene, dSVIP, in the absence of one transcription factor, but not both. Mechanistically, intestinal overexpression of dSVIP leads to nuclear accumulation of DAF-16 and HLH-30 in gut and non-gut tissues and triggers global gene expression changes, including induction of vps-34 and related lipid-metabolism genes, that promote tubular-lysosome activity. Collectively, our work reveals a cellular process under control of DAF-16 and HLH-30 that elicits pro-health effects in aging.
    DOI:  https://doi.org/10.1038/s41467-025-64832-x
  4. J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):
    Sphingolipid and methionine metabolism in aging.
    Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.
      Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.
    Keywords:  Aging; Metabolism; Methionine; Sphingolipids
    DOI:  https://doi.org/10.1242/jcs.264026
  5. Int J Mol Sci. 2025 Nov 06. pii: 10800. [Epub ahead of print]26(21):
    Ceramide as a Biomarker for HFpEF in Women: Menopause, Aging, and Pregnancy.
    Ruth R Magaye, David M Kaye, Bing H Wang.
      Heart failure with preserved ejection fraction (HFpEF) currently accounts for half of the heart failure (HF) cases world-wide, affecting nearly 32 million people. HFpEF has a skewed prevalence toward females and those older than 65 years old. The pathophysiology of HFpEF is suggestive of a conglomerate of inflammatory, hypertensive, as well as metabolic dysfunction, giving rise to the syndrome. Disruptions in ceramide metabolism do occur in heart failure as well as within the HFpEF-associated risk factors, both modifiable inflammation, obesity, hypertension, diabetes, and non-modifiable-aging, and female sex. The focus of this review is to draw attention to the links between changes in female biophysiology, such as pregnancy, menopause and aging, in which ceramide is dysregulated and consequently gives rise to the same pathologies that are labeled as risk factors for HFpEF. Our objective is to highlight ceramides as potential biomarkers for prevention and initial diagnostic tools for HFpEF, especially for women later in life.
    Keywords:  aging; ceramides; females; heart failure with preserved ejection fraction; hypertension; obesity
    DOI:  https://doi.org/10.3390/ijms262110800
  6. FEBS Open Bio. 2025 Nov 10.
    Autophagosome marker, LC3, is released extracellularly via several distinct pathways.
    Koki Saito, Masashi Arakawa, Koki Maeda, Eiji Morita.
      Autophagy-mediated secretion contributes to the maintenance of intracellular homeostasis by releasing cytoplasmic components into the extracellular space. However, several aspects of the process remain unclear. In this study, we developed an ultrasensitive detection system using HiBiT tag/NanoBiT technology to analyze the conditions that trigger the secretion of LC3, an autophagosome marker. In HiBiT-tagged knock-in cells, a detectable amount of HiBiT-dependent NanoLuc luciferase activity (HiBiT activity) from HiBiT-fused LC3 was observed in the culture supernatants. However, the levels were lower than those of CD63. HiBiT activity was detected only in the presence of detergent, indicating that LC3 was released from the lipid membranes. Treatment with bafilomycin A1 significantly increased the extracellular HiBiT activity, which was diminished in ATG5 or FIP200 knockout cells, suggesting that this release depends on autophagosome formation. However, some HiBiT-LC3 was detected in these knockout cells, indicating that LC3 may be released via an autophagy-independent mechanism. The introduction of a C-terminal truncation (ΔG) or the K51A/L53A mutation also reduced LC3 release, but did not completely inhibit it, suggesting that multiple pathways exist for LC3 release. This system is expected to elucidate the mechanisms underlying autophagy-mediated secretion.
    Keywords:  HiBiT tag; LC3 family; autophagic secretion; autophagy; knock‐in cells; lysosome
    DOI:  https://doi.org/10.1002/2211-5463.70150
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒16 at 2:37.