bims-lypmec 2024-06-09 papers

ACS Nano. 2024 Jun 03.

Acidic Nanoparticles Restore Lysosomal Acidification and Rescue Metabolic Dysfunction in Pancreatic β-Cells under Lipotoxic Conditions.

Chih Hung Lo, Lance M O'Connor, Gavin Wen Zhao Loi, Eka Norfaishanty Saipuljumri, Jonathan Indajang, Kaitlynn M Lopes, Orian S Shirihai, Mark W Grinstaff, Jialiu Zeng.

Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) polyesters, comprising a 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical with diameters of ≈100 nm and have low polydispersity and good stability. Notably, TFSA NPs, which are composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying properties. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets, INS-1 β-cells under chronic lipotoxic conditions, and pancreatic tissues of high-fat-diet (HFD) mice. Treatment with TFSA NPs restores lysosomal acidification, autophagic function, and mitochondrial activity, thereby improving the pancreatic function in INS-1 cells and HFD mice with lipid overload. Importantly, the administration of TFSA NPs to HFD mice reduces insulin resistance and improves glucose clearance. These findings highlight the therapeutic potential of lysosome-acidifying TFSA NPs for T2D.

Keywords: Type 2 diabetes (T2D); V-ATPase; acidic nanoparticles; autophagic degradation; insulin secretion; lysosomal acidification; mitochondrial function

DOI: https://doi.org/10.1021/acsnano.3c09206

Trends Cell Biol. 2024 Jun 06. pii: S0962-8924(24)00111-9. [Epub ahead of print]

Lysosomal control of the cGAS-STING signaling.

Yinfeng Xu, Wei Wan.

The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders.

Keywords: STING; autophagy; cGAS; human disorders; innate immunity; lysosome

DOI: https://doi.org/10.1016/j.tcb.2024.05.004

Nat Cell Biol. 2024 Jun 05.

MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes.

The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1-GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.

DOI: https://doi.org/10.1038/s41556-024-01436-5

J Pharmacol Exp Ther. 2024 Jun 04. pii: JPET-AR-2023-001981. [Epub ahead of print]

Rapamycin and Starvation MitigateIndomethacin-Induced Intestinal Damage through Preservationof Lysosomal VacuolarATPase Integrity.

Makoto Shirakawa, Shunichi Yokoe, Takatoshi Nakagawa, Kazumasa Moriwaki, Toshihisa Takeuchi, Michio Asahi.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, antipyretic, and analgesic properties and are among the most commonly used drugs. Although the cause of NSAID-induced gastric ulcers is well-understood, the mechanism behind small intestinal ulcers remains elusive. In this study, we examined the mechanism through which indomethacin (IM), a prominent NSAID, induces small intestinal ulcers, both in vitro and in vivo In IEC6 cells, a small intestinal epithelial cell line, IM treatment elevated levels of LC3-Ⅱ and p62. These expression levels remained unaltered after treatment with chloroquine or bafilomycin, which are vacuolar ATPase (V-ATPase) inhibitors. IM treatment reduced the activity of cathepsin B, a lysosomal protein hydrolytic enzyme, and increased the lysosomal pH. There was a notable increase in subcellular co-localization of LC3 with Lamp2, a lysosome marker, post-IM treatment. The increased lysosomal pH and decreased cathepsin B activity were reversed by pretreatment with rapamycin (Rapa) or glucose starvation, both of which stabilize V-ATPase assembly. To validate the in vitro findings in vivo, we established an IM-induced small intestine ulcer mouse model. In this model, we observed multiple ulcerations and heightened inflammation following IM administration. However, pretreatment with Rapa or fasting, which stabilize V-ATPase assembly, mitigated the IM-induced small intestinal ulcers in mice. Co-immunoprecipitation studies demonstrated that IM binds to V-ATPase in vitro and in vivo These findings suggest that IM induces small intestinal injury through lysosomal dysfunction, likely due to the disassembly of lysosomal V-ATPase caused by direct binding. Moreover, Rapa or starvation can prevent this injury by stabilizing the assembly. Significance Statement This study elucidates the largely unknown mechanisms behind small intestinal ulceration induced by indomethacin and reveals the involvement of lysosomal dysfunction via V-ATPase disassembly. The significance lies in identifying potential preventative interventions, such as rapamycin treatment or glucose starvation, offering pivotal insights that extend beyond NSAID-induced ulcers to broader gastrointestinal pathologies and treatments, thereby providing a foundation for novel therapeutic strategies aimed at a wide array of gastrointestinal disorders.

Keywords: gastrointestinal toxicology; non-steroidal anti-inflammatory drugs (NSAIDs)

DOI: https://doi.org/10.1124/jpet.123.001981

Sci Rep. 2024 06 05. 14(1): 12978

MARK4 aggravates cardiac dysfunction in mice with STZ-induced diabetic cardiomyopathy by regulating ACSL4-mediated myocardial lipid metabolism.

Yi Wu, Jingqi Zhang, Weiyi Wang, Dongdong Wu, Yang Kang, Lu Fu.

Diabetic cardiomyopathy is a specific type of cardiomyopathy. In DCM, glucose uptake and utilization are impaired due to insulin deficiency or resistance, and the heart relies more heavily on fatty acid oxidation for energy, resulting in myocardial lipid toxicity-related injury. MARK4 is a member of the AMPK-related kinase family, and improves ischaemic heart failure through microtubule detyrosination. However, the role of MARK4 in cardiac regulation of metabolism is unclear. In this study, after successful establishment of a diabetic cardiomyopathy model induced by streptozotocin and a high-fat diet, MARK4 expression was found to be significantly increased in STZ-induced DCM mice. After AAV9-shMARK4 was administered through the tail vein, decreased expression of MARK4 alleviated diabetic myocardial damage, reduced oxidative stress and apoptosis, and facilitated cardiomyocyte mitochondrial fusion, and promoted myocardial lipid oxidation metabolism. In addition, through the RNA-seq analysis of differentially expressed genes, we found that MARK4 deficiency promoted lipid decomposition and oxidative metabolism by downregulating the expression of ACSL4, thus reducing myocardial lipid accumulation in the STZ-induced DCM model.

DOI: https://doi.org/10.1038/s41598-024-64006-7