bims-lypmec 2026-09-20 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2026–09–20
seven papers selected by
Satoru Kobayashi, New York Institute of Technology

DFCP1-containing ER microdomains mediate lysosomal membrane repair.
Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.
Lysosomal dysfunction in vascular smooth muscle cells: Mechanisms and therapeutic targets in vascular disease.
Inulin- and Butyrate-Mediated HIF-1α Butyrylation Prevent Diabetic Ferroptosis and Cardiomyopathy by Maintaining Iron Homeostasis.
Lysosomal signaling pathways influence heart rhythm, and regulate atrial function.

Nat Cell Biol. 2026 Sep 15.

DFCP1-containing ER microdomains mediate lysosomal membrane repair.

Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.

Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.

DOI: https://doi.org/10.1038/s41556-026-02062-z
Cells. 2026 Aug 27. pii: 1548. [Epub ahead of print]15(17):

Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.

Lingling Cheng, Gaojie Song.

  Aging mesenchymal stem/stromal cells (MSCs) lose regenerative capacity as redox imbalance, mitochondrial damage, defective organelle quality control and chronic inflammation converge. Yet these processes are commonly considered in isolation, obscuring whether damaged mitochondrial cargo reaches lysosomes and is ultimately degraded. Here, we define mitochondria-lysosome quality flux (MLQF) as an author-proposed, evidence-graded framework that tracks mitochondrial damage from recognition and sorting through lysosomal delivery to terminal lysosomal degradation in aging MSCs. The framework explicitly separates delivery to an acidic compartment from completed degradation and distinguishes direct MSC evidence from cross-model mechanisms and candidate pathways. MSC studies most strongly support macroautophagy-dependent mitophagy, particularly when assessed using dynamic flux reporters. By contrast, mitochondria-derived vesicles and microautophagy-like or piecemeal routes remain incompletely validated in MSCs. Studies in non-MSC systems further show that mitochondria-lysosome contact sites can support lysosomal acidification, although their contribution to natural MSC aging remains unresolved. By locating rate-limiting defects across this continuum, MLQF provides a testable basis for linking incomplete mitochondrial clearance to inflammatory signaling, lineage drift and regenerative decline, and for selecting bottleneck-matched interventions.

Keywords:  cellular senescence; mesenchymal stem/stromal cells; mitochondrial quality control; mitochondria–lysosome quality flux; mitophagy

DOI:  https://doi.org/10.3390/cells15171548
Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):

Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.

Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.

Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.

DOI: https://doi.org/10.1038/s41467-026-77423-1
Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2616684123

Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.

Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.

  Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.

Keywords:  SREBP; de novo lipogenesis; lysosomal enzyme transport; protein myristoylation; proximity labeling

DOI:  https://doi.org/10.1073/pnas.2616684123
Atherosclerosis. 2026 Sep 14. pii: S0021-9150(26)01267-0. [Epub ahead of print]422 121901

Lysosomal dysfunction in vascular smooth muscle cells: Mechanisms and therapeutic targets in vascular disease.

Qi Zhu, Wa Du, Chenran Wang, Matthew Corriere, Yanbo Fan.

  Vascular smooth muscle cell (VSMC) dysfunction is a common feature of atherosclerosis, aortic aneurysms, vascular calcification, and other vascular diseases. In VSMCs, lysosomes play an essential role in autophagic degradation, endocytic cargo processing, intracellular recycling, and cellular stress responses. Under pathological conditions, lysosomal dysfunction promotes foam cell formation, osteogenic differentiation, and extracellular matrix remodeling in VSMCs, thereby contributing to vascular diseases. This review summarizes current evidence on the role of lysosomal dysfunction in VSMC biology, its contribution to vascular diseases, and the molecular mechanisms involved. We also discuss strategies to restore lysosomal function and the challenges of targeting lysosomal pathways in VSMCs. A better understanding of VSMC-specific lysosomal regulation may facilitate the development of therapeutic strategies for vascular diseases.

Keywords:  Aortic aneurysm; Atherosclerosis; Autophagy; Lysosome dysfunction; Vascular calcification; Vascular disease; Vascular smooth muscle cells

DOI:  https://doi.org/10.1016/j.atherosclerosis.2026.121901
Diabetes. 2026 Sep 15. pii: db260063. [Epub ahead of print]

Inulin- and Butyrate-Mediated HIF-1α Butyrylation Prevent Diabetic Ferroptosis and Cardiomyopathy by Maintaining Iron Homeostasis.

Ge Yang, Yuan Tian, Rui Sun, Chao Dong, Yanru Li, Shuang Li, Haiying Zhang, Ying Xin.

ARTICLE HIGHLIGHTS: Dysregulated iron metabolism and ferroptosis contribute to diabetic cardiomyopathy (DCM); however, the regulatory mechanisms and effective therapeutic strategies remain elusive. We sought to identify the role of hypoxia-inducible factor 1α (HIF-1α) in regulating myocardial iron homeostasis and ferroptosis in DCM, as well as evaluate the preventive effects of inulin on ferroptosis-induced DCM and elucidate its mechanism. Inulin-fermented butyrate activates the HIF-1α-ferritin heavy chain (FTH)/mitochondrial ferritin (FTMT) axis, alleviating cardiac ferroptosis and DCM, and stabilizes HIF-1α by promoting K190 Kbu modification and inhibiting ubiquitin-dependent degradation. Targeting the HIF-1α-FTH/FTMT axis via inulin, butyrate, or alternative approaches may represent a promising therapeutic strategy for alleviating DCM and other diabetes complications.

DOI: https://doi.org/10.2337/db26-0063
Cardiovasc Res. 2026 Sep 19. pii: cvag207. [Epub ahead of print]

Lysosomal signaling pathways influence heart rhythm, and regulate atrial function.

Emily Akerman, Rebecca A Capel, Eva A Rog-Zielinska, Annika Winbo, Daniel Aston, Florian Falter, Razik Bin Abdul Mu-U-Min, Matthew J Read, Samuel J Bose, Pawel Swietach, Jingyu Wang, Alexander D Corbett, Andreas Koschinski, Serena Calamaio, Dario Melgari, Rachele Prevostini, Ilaria Rivolta, Thamali Ayagama, Ifan Jenkin, Jillian N Simon, Funsho E Fakuade, Julius R Pronto, Parveen Sharma, Charlotte Melia, Qianqian Song, Martin J Booth, Frances M Platt, Ming Lei, Svenja Hester, Roman Fischer, Niels Voigt, Ulrich Schotten, Sander Verheule, Aiswarya Dev, Marie Held, Thomas Waring, Antony Galione, Marco Keller, Franz Bracher, Manuela Zaccolo, Derek A Terrar, Rebecca A B Burton.

AIMS: In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum (SR) Ca2+ sequestration, producing larger Ca2+ transients. However, the role of lysosomal Ca2+ signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated.
METHODS AND RESULTS: Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signaling microdomains between lysosomes and neighboring SR or mitochondria in mouse, and goat tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3'-5'-cyclic adenosine monophosphate (cAMP) in response to lysosomal signaling, adding a novel trigger for cyclic nucleotide signaling.
CONCLUSIONS: Our findings support the hypothesis that lysosomal Ca2+ signaling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.

DOI: https://doi.org/10.1093/cvr/cvag207