bims-cesemi 2026-10-11 papers

J Invest Dermatol. 2026 Oct 08. pii: S0022-202X(26)03768-1. [Epub ahead of print]

Mitochondrial calcium depletion in Darier disease is rescued by dantrolene sodium partly via MCU.

Nuoqi Wang, Matthew Hunt, Zhuofei Ye, Etty Bachar-Wikstrom, Jakob D Wikstrom.

Darier disease (DD), caused by ATP2A2 mutations, disrupts epidermal adhesion via endoplasmic reticulum (ER) calcium defects. While ER calcium depletion is documented, its impact on mitochondrial calcium homeostasis remains unknown. This study investigates mitochondrial calcium downregulation in DD and evaluates repurposing the ryanodine receptor (RyR) antagonist dantrolene to restore mitochondrial function. Using primary, immortalised DD and ATP2A2 knockout keratinocytes as well as patient fibroblasts, we measured mitochondrial morphology and calcium level. DD models showed fragmented mitochondria and diminished respiratory function. These changes were associated with significantly lower mitochondrial calcium in keratinocytes. Dantrolene increased mitochondrial calcium uptake, partly via the mitochondrial calcium uniporter (MCU), enhancing TCA cycle enzyme activity and improving mitochondrial respiration. This recovery strengthened cell-cell adhesion in DD keratinocytes. Mitochondrial calcium reduction is a critical mediator in DD. Dantrolene ameliorates this calcium dyshomeostasis and disease phenotypes, proposing a therapeutic strategy using an FDA-approved drug.

Keywords: Darier disease; MCU; SERCA2; dantrolene; mitochondrial calcium

DOI: https://doi.org/10.1016/j.jid.2026.08.031

bioRxiv. 2026 Aug 10. pii: 2026.08.08.743614. [Epub ahead of print]

Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function.

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

DOI: https://doi.org/10.64898/2026.08.08.743614

Nat Metab. 2026 Oct 07.

Inhibiting fructose metabolism to treat fatty liver.

Richard J Johnson, Miguel A Lanaspa, Dean R Tolan.

DOI: https://doi.org/10.1038/s42255-026-01627-4

Science. 2026 Oct 08. 394(6820): eadx9628

Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.

Mitochondria are dynamic organelles that remodel their shape to regulate cell fate. Mitochondrial division involves interactions with the endoplasmic reticulum (ER), lysosomes, and trans-Golgi network-derived vesicles to facilitate membrane scission. How interorganelle contacts regulate mitochondrial membrane fusion remains largely unknown. Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites. Accordingly, loss of class II PI3-kinase isoforms α and β (PI3K-C2α and PI3K-C2β), which generate PI(3,4)P2, led to mitochondrial fragmentation resulting from impaired fusion. Furthermore, cardiomyocyte-specific PI3K-C2α and PI3K-C2β double-deletion mice exhibited mitochondrial fragmentation and heart failure. Thus, subpopulations of Golgi-derived vesicles carrying different phosphoinositides control mitochondrial membrane remodeling and homeostasis.

DOI: https://doi.org/10.1126/science.adx9628

Front Aging. 2026 ;7 1866906

Unraveling skeletal muscle senescence in an in vitro cell culture model.

Kayo Moreira Bagri, Morgana Teixeira Lima Castelo-Branco, Claudia Mermelstein.

Introduction: Skeletal muscles are crucial for voluntary movement, posture, breathing, joint stability, and therefore are essential for maintaining overall health and quality of life. Aging, sarcopenia, cancer, immobilization, and several muscle pathologies can have an impact on muscle function, and muscle cell senescence is associated with these conditions.
Methods: Here we aimed to develop a primary cell culture model to study skeletal muscle cell senescence. We induced cell cycle arrest in cultured embryonic chick muscle cells using a low concentration of cytosine arabinoside (Ara-C) for 9 days.
Results: Our results show that Ara-C was able to induce several cellular senescence-associated bone fide characteristics, including reduced cell proliferation, increased β-galactosidase expression, increased reactive oxygen species production (ROS), increased p53 and p21 expression, increased muscle fibroblast cell size and nuclei numbers, increased lysosomal activity, decreased muscle differentiation (decreased muscle fiber size and decreased desmin expression), and increased secretion of IL-6, TNFα and TGFβ. Interestingly, inhibition of fibroblast growth factor receptor recovers the AraC-induced senescent phenotype in myogenic cells.
Conclusion: This new experimental model could be used to deepen our understanding of the molecules and signaling pathways associated with the initiation and establishment of skeletal muscle senescence. Furthermore, this model could be used to test new drugs and therapeutic interventions aiming the amelioration of senescence-associated conditions.

Keywords: FGF; ROS; cytosine arabinoside; desmin; lysosomes; muscle; p53; senescence

DOI: https://doi.org/10.3389/fragi.2026.1866906