IP₃ receptor (IP₃R)-mediated Ca²⁺ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca²⁺ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson’s disease (PD). The dependence of Ca²⁺ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca²⁺ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca²⁺ transfer and mitochondrial oxidative metabolism due to enrichment of IP₃R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca²⁺ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca²⁺ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca²⁺ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

Background/Objectives: Methyltransferase EZH2-mediated H3K27me3 is involved in liver inflammation and fibrosis, but its role in hepatic metabolic derangements is not yet clearly defined. We investigated if a high-fat diet (HFD) induced early changes in EZH2 expression and H3K27 me3 in the liver of mice. Methods: Five-week-old mice were fed an HFD or a low-fat diet (Control) for 2 weeks (2 W) or 8 weeks (8 W). Body weight was recorded weekly. Glycemia and oral glucose tolerance were assessed at baseline and after 2 W–8 W. Finally, livers were collected for further analysis. Results: As expected, mice that received 8 W HFD showed an increase in body weight, glycemia, and liver steatosis and an impairment in glucose tolerance; no alterations were observed in 2 W HFD mice. Eight weeks of HFD caused hepatic EZH2 nuclear localization and increased H3 K27me3; surprisingly, the same alterations occurred in 2 W HFD mice livers, even before overweight onset. We demonstrated that selective EZH2 inhibition reduced H3K27me3 and counteracted lipid accumulation in HUH-7 cells upon palmitic acid treatment. Conclusions: In conclusion, we point to EZH2/H3K27me3 as an early epigenetic event occurring in fatty-acid-challenged livers both in vivo and in vitro, thus establishing EZH2 as a potential pharmacological target for metabolic derangements.

Geckos (Gekkota), the species-rich clade of reptiles with more than 2200 currently recognized species, demonstrate a remarkable variability in diploid chromosome numbers (2n = 16–48) and mode of sex determination. However, only a small fraction of gekkotan species have been studied with cytogenetic methods. Here, we applied both conventional (karyotype reconstruction and C-banding) and molecular (fluorescence in situ hybridization with probes for rDNA loci and telomeric repeats) cytogenetic analyses in seven species of geckos, namely Blaesodactylus boivini, Chondrodactylus laevigatus, Gekko badenii, Gekko cf. lionotum, Hemidactylus sahgali, Homopholis wahlbergii (Gekkonidae) and Ptyodactylus togoensis (Phyllodactylidae), in order to provide further insights into the evolution of karyotypes in geckos. Our analysis revealed the presence of interstitial telomeric repeats in four species, but we were not able to conclude if they are remnants of previous chromosome rearrangements or were formed by an accumulation of telomeric-like satellite motifs. Even though sex chromosomes were previously identified in several species from the genera Hemidactylus and Gekko by cytogenetic and/or genomic methods, they were not detected by us in any examined species. Our examined species either have poorly differentiated sex chromosomes or, possibly, environmental sex determination. Future studies should explore the effect of temperature and conduct genome-wide analyses in order to identify the mode of sex determination in these species.

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid homeostasis, neuroactive steroid deficiency (notably allopregnanolone, ALLO), and gut–brain axis alterations. Objective: This study aimed to investigate the effects of finasteride withdrawal (FW) in a rat model and evaluate the potential protective effects of ALLO on gut and hypothalamic inflammation. Methods: Adult male Sprague Dawley rats were treated with finasteride for 20 days, followed by one month of drug withdrawal. A subgroup received ALLO treatment during the withdrawal. Histological, molecular, and biochemical analyses were performed on the colon and hypothalamus. Gut microbiota-derived metabolites and markers of neuroinflammation and blood–brain barrier (BBB) integrity were also assessed. Results: At FW, rats exhibited significant colonic inflammation, including a 4.3-fold increase in Mφ1 levels (p < 0.001), a 2.31-fold decrease in butyrate concentration (p < 0.01), and elevated hypothalamic GFAP and Iba-1 protein expression (+360%, p < 0.01 and +100%, p < 0.01, respectively). ALLO treatment rescued these parameters in both the colon and hypothalamus but only partially restored mucosal and BBB structural integrity, as well as the NF-κB/PPARγ pathway. Conclusions: This preclinical study shows that FW causes inflammation in both the gut and hypothalamus in rats. ALLO treatment helped reduce several of these effects. These results suggest ALLO could have a protective role and have potential as a treatment for PFS patients.

Glycogen synthase kinase-3β (GSK3β), primarily described as a regulator of glycogen metabolism, is a molecular hub linking numerous signaling pathways and regulates many cellular processes like cytoskeletal rearrangement, cell migration, apoptosis, and proliferation. In neurons, the kinase is engaged in molecular events related to the strengthening and weakening of synapses, which is a subcellular manifestation of neuroplasticity. Dysregulation of GSK3β activity has been reported in many neuropsychiatric conditions, like schizophrenia, major depressive disorder, bipolar disorder, and Alzheimer’s disease. In this review, we describe the kinase action in reward circuit-related structures in health and disease. The effect of pharmaceuticals used in the treatment of addiction in the context of GSK3β activity is also discussed.