bims-lypmec 2025-12-14 papers

Int J Mol Sci. 2025 Nov 29. pii: 11581. [Epub ahead of print]26(23):

The lysosome is no longer viewed as a simple degradative "trash can" of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical "microreactor" that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5-5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective "safe house," yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome's broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody-drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine-thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies.

Keywords: acidic organelles; drug resistance; drug–lysosome interactions; fenton reaction; lysosome; lysosomotropic design; metal-mediated reactive oxygen species; therapeutic design principles

DOI: https://doi.org/10.3390/ijms262311581

J Mol Cell Cardiol Plus. 2025 Dec;14 100825

Metformin alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy.

Jordan S F Chan, Seyed Amirhossein Tabatabaei Dakhili, Nadeen R Wu, Magnus J Stenlund, Alexa N King, Linyue Dong, Indiresh A Mangra-Bala, Tanin Shafaati, Sally R Ferrari, Amanda A Greenwell, Kunyan Yang, Christina T Saed, Farah Eaton, Keshav Gopal, Gregory R Steinberg, Jason R B Dyck, John R Ussher.

The first line therapy for managing type 2 diabetes (T2D), metformin, has been shown to be cardioprotective in humans and several preclinical models of cardiovascular disease. However, there has been limited interrogation into metformin's effects on diastolic function, a hallmark characteristic of diabetic cardiomyopathy (DbCM), which is becoming increasingly prevalent in people with pre- and early-stage T2D. Accordingly, we aimed to determine the effects of metformin on the pathogenesis of DbCM and hypothesized that treatment with metformin would alleviate diastolic dysfunction in mice with T2D. To induce experimental T2D and DbCM, male C57BL/6J mice were fed a high-fat diet for 12.5 weeks, in combination with a single, low-dose injection of streptozotocin (75 mg/kg) at week 4.5. The animals' drinking water was randomized to include either vehicle control or metformin (3.0 g/L) during the final 7.5 weeks. As expected, metformin treatment improved glycemia with a trend towards a reduction in adiposity in mice with T2D. Using ultrasound echocardiography, we observed that metformin improved diastolic function in mice with T2D as reflected by an increase and a decrease in the e'/a' and E/e' ratios, respectively. Furthermore, wheat-germ agglutinin staining indicated that treatment with metformin decreased cardiomyocyte hypertrophy in mice with T2D. However, mice with T2D treated with metformin did not exhibit increases in myocardial adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Thus, our findings suggest that metformin has salutary actions against DbCM and its associated diastolic dysfunction, which may be independent of its ability to increase AMPK activity.

Keywords: Diabetic cardiomyopathy; Diastolic dysfunction; Metformin; Obesity; Type 2 diabetes

DOI: https://doi.org/10.1016/j.jmccpl.2025.100825

J Biochem. 2025 Dec 11. pii: mvaf080. [Epub ahead of print]

Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.

Akimitsu Konishi.

Cellular senescence is a stress-induced, stable growth arrest accompanied by marked metabolic alterations and acquisition of the senescence-associated secretory phenotype (SASP). While enhanced glycolysis, mitochondrial dysfunction, and lysosomal abnormalities are well-established features, emerging evidence identifies progressive intracellular acidification as an important yet underappreciated regulator of cellular senescence. Acidification results from suppressed NHE1-mediated proton efflux, elevated glycolytic proton production, and lysosomal membrane permeabilization. This lowered pH alters redox balance, inhibits HDAC activity, and promotes transcription of senescence-associated genes. Recent work by Kawakami et al. demonstrates that acidification activates a glycolysis-linked inflammatory circuit through accumulation of glucose-6-phosphate and induction of the MondoA targets TXNIP and ARRDC4, which correlate with SASP induction and define a highly secretory subset of senescent cells. These findings suggest that intracellular pH functions as a key metabolic cue linking altered glycolysis to inflammatory output, offering a conceptual framework that may guide future efforts to modulate age-associated chronic inflammation.

Keywords: Cellular senescence; Glycolysis; Inflammation; Intracellular acidification; Senescence-associated secretory phenotype (SASP)

DOI: https://doi.org/10.1093/jb/mvaf080

J Biol Chem. 2025 Dec 06. pii: S0021-9258(25)02868-6. [Epub ahead of print] 111016

Detection and quantitation of ferritinophagy using halo-tag tracing.

Sachin K Kempelingaiah, Alexandra J Straus, Grace Mavodza, Can E Senkal.

Iron is an essential element required for critical processes such as oxygen transport, energy generation, and DNA synthesis. To be incorporated as a cofactor, iron that is stored in the cytosol within ferritin needs to be liberated by ferritinophagy. Ferritinophagy is an autophagic process in which ferritin is targeted to the lysosomes, through its interaction with nuclear receptor coactivator 4 (NCOA4) for degradation and release of labile iron. Despite its involvement in neurodegenerative diseases, anemia, cancer, and insulin resistance, a specific and sensitive method to detect ferritinophagy has been lacking. To detect and quantitate ferritinophagic flux, we generated a Halo-tagged ferritin heavy chain 1 (FTH1) construct and took advantage of stabilization of Halo fragment in the presence of its fluorescently labelled ligand. Stably expressed Halo-FTH1 operated identical to its endogenous counterpart. More importantly, using pulse-chase settings lysosomal accumulation of Halo fragment after induction of ferritinophagy was detected and quantitated by in-gel fluorescence, immunoblotting, and microscopic analyses. Finally, we found that silencing of NCOA4 prevented accumulation of TMR-Halo fragment and degradation of endogenous FTH1 under ferritinophagic conditions, confirming the specificity of our assay. Together, the HaloTag-FTH1 tool we generated can be used to specifically detect and quantitate ferritinophagy in mammalian cells with a fluorescent Halo-ligand, and this approach can be instrumental in studies focusing on cellular iron metabolism.

Keywords: FTH1; Ferritin; Ferritinophagy; Halo-tag; NCOA4

DOI: https://doi.org/10.1016/j.jbc.2025.111016

Int J Mol Sci. 2025 Nov 28. pii: 11552. [Epub ahead of print]26(23):

Emerging Roles of Post-Translational Modifications in Metabolic Homeostasis and Type 2 Diabetes.

Yong Kyung Kim, Hyeongseok Kim.

Post-translational modifications (PTMs) provide an integrated regulatory layer that couples nutrient and hormonal signals to whole-body energy homeostasis across metabolic organs. PTMs modulate protein activity, localization, stability, and metabolic networks in a tissue- and state-specific manner. Through network remodeling, PTMs integrate receptor signaling with chromatin and organelle function and align transcriptional control with mitochondrial function, proteostasis, and membrane trafficking. PTM crosstalk connects kinase cascades, nutrient-sensing pathways, and ubiquitin-family modifiers to orchestrate gluconeogenesis, lipolysis, glucose uptake, thermogenesis, and insulin secretion in response to nutrient cues. The metabolic state regulates PTM enzymes through changes in cofactors, redox tone, and compartmentalization, and PTM-dependent changes in transcription and signaling feedback to metabolic tone. In obesity and diabetes, dysregulated post translational modification networks disrupt insulin receptor signaling, disturb organelle quality control, and impair beta cell function, which promotes insulin resistance and beta cell failure. Consequently, PTMs organize metabolic information flow and modulate tissue responses to overnutrition and metabolic stress. A systems-level understanding of PTMs clarifies mechanisms of whole-body energy homeostasis and supports the discovery of new therapeutic targets in metabolic disease.

Keywords: diabetes mellitus; insulin sensitivity; metabolic disorder; post-translational modification

DOI: https://doi.org/10.3390/ijms262311552