bims-lypmec 2026-03-01 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2026–03–01
nine papers selected by
Satoru Kobayashi, New York Institute of Technology

Microautophagy: current understanding of its molecular mechanisms and functions.
Microbial tryptophan metabolism activates host lysosomal activity to facilitate lipid breakdown.
Restoring Lysosomes in Adipose Tissue Macrophages Mitigates Obesity-Induced Inflammation and Insulin Resistance.
Cadmium-induced ATP6V0A1 destabilization impairs lysosomal function to disrupt hepatic lipid homeostasis.
The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.
TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.
Galectins: Role and Therapeutics in Diabetes and Diabetic Foot Ulcers.
STARD3 regulates lysosome positioning and contacts via a GSK3-controlled phosphorylation switch.

Autophagy Rep. 2026 ;5(1): 2626661

Microautophagy: current understanding of its molecular mechanisms and functions.

Yasuyoshi Sakai, Christian Behrends, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Ana Maria Cuervo, Fulvio Reggiori.

  Microautophagy (MI-autophagy) is an umbrella term for intracellular degradative pathways that entail the invagination or protrusion of the limiting membranes of endolysosomal compartments, that is, late endosomes and mammalian lysosomes or yeast and plant vacuoles, followed by pinching-off of the membrane into the lumen of the organelle. During these processes, the material specifically and nonspecifically targeted for degradation is sequestered within the invaginating or protuberating membrane. In contrast to macroautophagy, the molecular mechanisms underlying MI-autophagy are largely unknown due to their diversity and complexity in location, regulation and molecular machinery requirements. Here, we review recent progress in the field of MI-autophagy, describing the molecular basis and functions of the MI-autophagic pathways reported to date in eukaryotic cells, from yeast to mammalian and plant cells.

Keywords:  Endosomes; lysosomes; multivesicular bodies; organelle turnover; proteolysis; vacuole

DOI:  https://doi.org/10.1080/27694127.2026.2626661
PLoS Biol. 2026 Feb 26. 24(2): e3003685

Microbial tryptophan metabolism activates host lysosomal activity to facilitate lipid breakdown.

Kenan Zhang, Zihan Luo, Yan Chen, Yan Li, Lang Wang, Yanan Liu, Ruizhi Yang, Qian Li, Jiahao Zhao, Bin Qi, Zhao Shan.

Lysosomes are central to lipid metabolism, yet how gut microbiota-derived metabolites regulate lysosomal function to influence host lipid homeostasis remains unknown. Here, we identify a mechanism in which bacterial tryptophan metabolism activates lysosomal activity to promote lipid breakdown in Caenorhabditis elegans, and show that the bacterial tryptophan metabolite indole recapitulates these effects in mammalian hepatocytes. By developing a lysosomal-responsive lipid reporter in C. elegans to screen for bacterial metabolic states that modulate host lipid storage, we discover that Escherichia coli tryptophan catabolism via tryptophanase TnaA induces lysosomal lipid chaperone LBP-8, driving lipid mobilization. Moreover, tryptophan metabolite indole enhanced lysosomal acidification and degradation capacity, while genetic disruption of lysosomal regulators reversed these effects. Strikingly, bacterial tryptophan metabolism further promoted mitochondrial β-oxidation through lysosomal lipase activity. This pathway was conserved in mammalian hepatocytes, where E. coli-derived tryptophan metabolite indole enhances lysosomal function and reduce lipid accumulation. Our work uncovers microbiota-regulated lysosomal activation as a critical axis in lipid homeostasis, highlighting its potential as a therapeutic target for metabolic disorders linked to lysosomal dysfunction.

DOI: https://doi.org/10.1371/journal.pbio.3003685
Int J Mol Sci. 2026 Feb 12. pii: 1755. [Epub ahead of print]27(4):

Restoring Lysosomes in Adipose Tissue Macrophages Mitigates Obesity-Induced Inflammation and Insulin Resistance.

Jiyeon Chang, Ellen Budiono, Shindy Soedono, Xaviera Riani Yasasilka, SungWan Chun, Kae Won Cho.

  Adipose tissue macrophages (ATMs) are key mediators of obesity-induced inflammation and insulin resistance. However, the contribution of lysosomal dysfunction to ATM inflammatory activation remains poorly defined. Here, we characterized lysosomal structural and functional alterations in ATMs during obesity and examined whether pharmacological restoration of lysosomal function using 2-hydroxypropyl-β-cyclodextrin (HPβCD) ameliorates metabolic inflammation. In diet-induced obese C57BL/6J male mice, adipose tissue exhibited increased lysosomal abundance, accompanied by reduced cathepsin L+V expression, modestly increased lysosomal acid lipase levels, and decreased expression of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Despite expanded lysosomal content, ATMs displayed impaired lysosomal acidification, indicating functional lysosomal dysfunction. Intraperitoneal administration of HPβCD for two weeks significantly improved glucose tolerance and insulin sensitivity without affecting body weight. Flow cytometric analysis revealed reduced pro-inflammatory M1 ATMs and CD8+ T lymphocytes in visceral adipose tissue, whereas immune cell populations in subcutaneous adipose tissue, blood, and spleen remained unchanged. In vitro, HPβCD suppressed pro-inflammatory gene expression in both classically and metabolically activated macrophages and attenuated inflammatory responses induced by lysosomal stressors, including bafilomycin A1 and chloroquine, while restoring TFEB expression. Collectively, these findings demonstrate that obesity is associated with lysosomal dysfunction in ATMs and that restoration of lysosomal function alleviates adipose tissue inflammation and metabolic dysfunction, highlighting lysosomal regulation in ATMs as a potential therapeutic target for obesity-associated metabolic diseases.

Keywords:  adipose tissue macrophage; cyclodextrin; inflammation; lysosome; obesity

DOI:  https://doi.org/10.3390/ijms27041755
Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Feb 19. pii: S1388-1981(26)00019-3. [Epub ahead of print]1871(3): 159733

Cadmium-induced ATP6V0A1 destabilization impairs lysosomal function to disrupt hepatic lipid homeostasis.

Juan Huo, Kongdong Li, Haifeng Shi, Yongjuan Liu, Jie Gu.

  Chronic cadmium (Cd2+) exposure is epidemiologically linked to metabolic disorders like hypertriglyceridemia, but the precise mechanisms disrupting hepatic lipid metabolism are unclear. Lysosomal function, critical for lipid degradation via autophagy, represents a potential yet unexplored target in Cd2+-induced steatosis. We utilized multi-strain mouse models and human hepatocytes to investigate the effects Cd2+ exposure. Serum metabolomics and biochemical assays were employed to assess lipid profiles. The role of ATP6V0A1, a key subunit of the V-ATPase proton pump, was systematically examined using genetic approaches (knockdown and overexpression) in conjunction with lysosomal pH probes, autophagic flux assays, and protein stability measurements. Cd2+ exposure consistently induced hypertriglyceridemia in mice, accompanied by a significantly altered serum triglyceride metabolomic profile. In the liver, Cd2+ downregulated ATP6V0A1 protein, which impaired lysosomal acidification and thereby blocked autophagic flux. Mechanistically, Cd2+ did not affect ATP6V0A1 mRNA levels but promoted its protein degradation, which could be attenuated by inhibitors of both the proteasome and the autophagy-lysosomal pathway. Functionally, either pharmacological inhibition of lysosomal acidity or genetic knockdown of ATP6V0A1 recapitulated Cd2+-induced intracellular and secreted triglyceride accumulation. Crucially, overexpression of ATP6V0A1 rescued Cd2+-induced lysosomal dysfunction, restored autophagic flux, and normalized triglyceride levels. Our study uncovers a novel molecular pathway wherein Cd2+ post-transcriptionally destabilizes ATP6V0A1, which paradoxically leads to lysosomal dysfunction and autophagic block, ultimately driving hepatic triglyceride accumulation, thereby nominating ATP6V0A1 as a central regulator and potential therapeutic target for chemical-associated fatty liver disease.

Keywords:  ATP6V0A1; Autophagy; Cadmium; Liver; Lysosome; Triglyceride

DOI:  https://doi.org/10.1016/j.bbalip.2026.159733
Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00071-7. [Epub ahead of print]

The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.

Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna L Farber, Ryan G Gaudet.

  Lysosomal damage is an endogenous danger signal, but its significance for innate immunity and the specific signaling pathways it engages remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. We find that transient lysosomal damage elicits sub-lethal mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) maintains a barrier against wholesale mtDNA release. Priming with type II IFN (IFN-γ) induced the antibacterial factor APOL3, which, upon sensing lysosomal damage, targets mitochondria undergoing MOMP to selectively permeabilize the IMM, enhance mtDNA release, and potentiate downstream cGAS signaling. Biochemical and cellular reconstitution revealed that, analogous to its bactericidal detergent-like mechanism, APOL3 permeabilized the IMM by solubilizing cardiolipin. Our findings illustrate how cells enlist an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.

Keywords:  DNA; damage; innate immunity; interferon; intracellular bacteria; lysosome; mitochondrion; viruses

DOI:  https://doi.org/10.1016/j.molcel.2026.01.029
Mol Biol Cell. 2026 Feb 25. mbcE24030109

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.

Corey J Theodore, Lianna H Wagner, Kenneth G Campellone.

Autophagy is an intracellular degradation process that maintains homeostasis, responds to stress, and plays key roles in preventing aging and disease. Autophagosome biogenesis, vesicle rocketing, and autolysosome tubulation are controlled by multiple actin cytoskeletal factors, but the impact of actin assembly on completion of the autophagic degradation pathway is not well understood. Here we studied autophagosomes and lysosomes in mouse fibroblasts harboring an inducible knockout (iKO) of the Arp2/3 complex, an essential actin nucleator. Arp2/3 complex ablation resulted in increased basal levels of autophagy receptors and lipidated membrane proteins from the LC3 and GABARAP families. Such phenotypes were accompanied by the steady-state presence of abnormally high numbers of autolysosomes and an inability of the Arp2/3 complex-deficient cells to complete autolysosome turnover due to lysosomal damage. When normal cells were treated with a lysosomal membrane-disrupting agent, the Arp2/3-activating protein WHAMM was recruited to lysosomes, and Arp2/3 complex activity was required for restoring intact lysosomal structure. Deletion of WHAMM in mouse or human fibroblasts decreased Arp2/3 localization to lysosomes and increased lysosomal damage. These results reveal the importance of the Arp2/3 complex and WHAMM for autophagic degradation and uncover a new role for the actin nucleation machinery in maintaining lysosomal integrity.

DOI: https://doi.org/10.1091/mbc.E24-03-0109
Acta Pharmacol Sin. 2026 Feb 25.

TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.

Chen Chen, Han Lou, An-Ge Hu, Qiang Huang, Ling-Yi Kong, Zhou-Xiu Chen, Heng-Hui Xu, Yong-Chao Chen, Heng Liu, Shu-Qin Duan, Yuan Lin, Li-Min Zhao, Ling Liu, Muneer Ahmed Khoso, Xin Liu, Yong Zhang.

  Lysosomal dysfunction exacerbates cardiomyocyte damage in myocardial infarction (MI) by impairing cellular degradation. However, the precise molecular mechanisms driving this pathologic process remain unclear. Lysosomal transmembrane protein 175 (TMEM175) is critical for regulating lysosomal homeostasis. But its pathophysiological implications in post-infarction cardiac dysfunction are not fully understood. By using both gain and loss of function approaches in vivo and in vitro, we discovered that TMEM175 overexpression conferred cardioprotection in MI models. This was evidenced by reduced infarct size, collagen deposition, and myocardial injury, accompanied by restored lysosomal function characterized by increased biogenesis, normalized pH, enzyme activities, and autophagic flux. Conversely, TMEM175 knockdown exacerbated these pathologies. Under hypoxic stress, TMEM175 overexpression in neonatal mouse cardiomyocytes (NMCMs) improved cell viability and corrected lysosomal dysfunction, whereas its knockdown worsened the aforementioned effects. Mechanistically, the reduction of TMEM175 induced by MI increases mammalian target of rapamycin complex 1 (mTORC1) phosphorylation on lysosomal membranes and suppresses the nuclear translocation of transcription factor EB (TFEB), thereby impairing TFEB's transcriptional regulation of lysosome-associated genes. Meanwhile, TMEM175 restoration reversing this cascade, and restoring lysosomal function and autophagic flux.

Keywords:  TFEB; TMEM175; lysosome; mTORC1; myocardial infarction

DOI:  https://doi.org/10.1038/s41401-026-01749-1
Biomolecules. 2026 Feb 03. pii: 232. [Epub ahead of print]16(2):

Galectins: Role and Therapeutics in Diabetes and Diabetic Foot Ulcers.

Alhasan Alobaidi, Rawan Al Judeid, Vikrant Rai.

  Diabetes is a chronic inflammatory disease due to decreased insulin release or insulin resistance. Diabetes complications stem from high blood sugar damaging blood vessels and nerves, leading to issues like heart disease, stroke, kidney failure, nerve damage, vision loss, foot ulcers, gum disease, skin infections, and digestive/bladder issues. Galectins, especially galectin-3, are emerging as key players in diabetes complications, promoting fibrosis, inflammation, and vascular damage. This suggests that galectins may be potential therapeutic targets in diabetes and its complications, and a need to understand their role and therapeutic potential. The objective of this review is to synthesize current evidence on galectin biology in diabetes mellitus (mainly on type II diabetes) and DFUs, delineate their mechanistic roles in metabolic dysfunction and wound healing, summarize findings from human and preclinical studies, and evaluate emerging diagnostic and therapeutic strategies. Finally, this review highlights key gaps that must be addressed to advance clinical translation. The literature search suggests that galectins play a critical role in the pathogenesis of diabetes and related complications and may be potential therapeutic targets.

Keywords:  diabetes; diabetic complications; diabetic foot ulcers; galectins; therapeutic targets

DOI:  https://doi.org/10.3390/biom16020232
EMBO J. 2026 Feb 25.

STARD3 regulates lysosome positioning and contacts via a GSK3-controlled phosphorylation switch.

Julie Eichler, Corinne Wendling, Sophie Huver, Mehdi Zouiouich, Victor Hanss, Anna Cardinal, Victoria Fimbel, Catherine Birck, Alastair G McEwen, Céline Knorr, Catherine Fromental-Ramain, Maxime Boutry, Marie-Pierre Chenard, Guillaume Drin, Catherine Tomasetto, Fabien Alpy.

  Membrane contact sites (MCS) are dynamic regions where the membranes of two organelles come into close apposition. MCSs play many roles in cellular homeostasis by facilitating inter-organelle lipid exchange and organelle positioning. The late endosome/lysosome (LE/Lys) cholesterol transfer protein STARD3 forms reversible contacts between LE/Lys and the endoplasmic reticulum (ER). This tether protein contains a Phospho-FFAT motif (two phenylalanines in an acidic tract) whose interaction with ER-resident VAPs (vesicle-associated membrane protein-associated proteins) is phosphorylation-dependent. In this study, we identify GSK3α and GSK3β as the kinases responsible for phosphorylating serine 209 within the Phospho-FFAT motif of STARD3. This phosphorylation event is both necessary and sufficient to activate STARD3's tethering activity, thereby promoting ER-LE/Lys contacts. Furthermore, we show that when ER-LE/Lys tethering is prevented, STARD3 triggers LE/Lys homotypic interactions, revealing an additional function for STARD3 on endosome biology. Our findings establish a direct and critical role for GSK3 in regulating MCS via STARD3 phosphorylation, and expand our understanding of the molecular basis of inter-organelle communication.

Keywords:  Endoplasmic Reticulum; Endosome; Lipid Transfer Protein; Membrane Contact Site; Phosphorylation

DOI:  https://doi.org/10.1038/s44318-026-00705-3