Journal of Cellular Physiology最新文献

GPR39, a zinc-sensing receptor, is essential for bone homeostasis in male mice through regulation of osteoblast function and matrix composition. This study examined the effects of GPR39 deficiency in female mice using both global and osteoblast lineage-specific GPR39 knockout models (Gpr39^Ob−/Ob−). In vivo, GPR39-deficient female mice exhibited reduced bone mass, increased mineralization rates, and significantly lower and more variable serum levels of pro-collagen type I N-propeptide (PINP), indicating impaired collagen synthesis and matrix remodeling. OVX models further demonstrated that GPR39 deficiency exacerbates estrogen-deficiency-induced bone loss, highlighting its protective role in postmenopausal-like states. Osteoblast lineage-specific GPR39 deletion replicated the skeletal abnormalities observed in global knockouts, revealing that GPR39 activity in the osteoblast lineage is indispensable for proper collagen deposition and mineralization. Western blot analysis of Gpr39^Ob−/Ob− osteoblasts confirmed reduced extracellular collagen levels, while quantitative mRNA analysis of Col1a2 revealed zinc signaling through GPR39 as a key regulator of collagen production. Zinc-induced Col1a2 expression, dependent on GPR39 and mediated via Gα_q signaling, was abolished in GPR39-deficient osteoblasts. These findings provide insights into how zinc signaling via GPR39 regulates osteoblast function and collagen synthesis, emphasizing its role in maintaining matrix composition. Targeting GPR39 may offer novel therapeutic strategies for osteoporosis and other bone disorders characterized by impaired matrix remodeling.

Two main influencing factors of human soft tissue healing are concomitant diseases and cellular senescence, both accumulating with increasing age. Due to the raising population of the elderly in western countries, it is essential to enhance the level of knowledge concerning the function of senescence in a granulation tissue during repair. The present study was intended to verify classic markers of senescence, like senescence-associated ß-galactosidase and the development of a senescence-associated secretory phenotype among fibroblasts during emerging senescence. The application of an in vitro model using serial passaging as inducer of replicative senescence revealed specific differences of a non-senescent and a pre-senescent fibroblast phenotype in mono-cultures, representing the basis for a detailed examination of the phenotypes in their interaction with microvascular endothelial cells in co-cultures. The results deliver new insights into the age dependent process of tissue repair. Characteristics of pre-senescent fibroblasts in terms of modified proliferation, cell morphology, cell cycle regulation, myofibroblastoid differentiation and cytokine release indicate a strong responsibility of this phenotype for the composition and function of a granulation tissue at different locations, including vascular sites. In its entirety, the results support the assumption, that a missing clearance of the senescence phenotype in late stages of tissue repair is one of the main reasons for healing failure.

The rhomboid superfamily, comprising both proteases and pseudoproteases, has emerged as a central regulator of membrane biology, mediating diverse functions including protein quality control, signal transduction, trafficking, and more. While molecular mechanisms of rhomboid activity have been well-characterized in invertebrate and cell-based systems, their physiological role in vertebrate development remains limited and continues to evolve. Here, we review recent advances in cell culture systems and vertebrate models that uncover the developmental and disease-relevant functions of rhomboid family members, including RHBDLs, iRhoms, PARL, and Derlins. We outline their roles in embryogenesis, tissue regeneration, neurodevelopment, and immune signaling, alongside their pathological involvement in cancer, neurodegeneration, and metabolic disorders. We also emphasize the limitations posed by early embryonic lethality in knockout models and advocate for tissue-specific vertebrate models to dissect rhomboid-dependent pathways in vivo. Understanding how rhomboid proteins coordinate developmental processes will not only reveal fundamental principles of membrane-associated processes, but also open new avenues for therapeutic targeting in disease.

Mitochondrial function plays a central role in regulating immunological and metabolic processes, particularly during successful aging. This cross-sectional study aimed to investigate associations between mitochondrial respiration of peripheral blood mononuclear cells (PBMCs; MR_PBMC) and key markers of immune function, systemic inflammation, and metabolic health in a cohort of healthy older adults. Sixteen healthy, physically active participants aged > 55 years (male: n = 9; female: n = 7; age: 64 ± 3.7 years; BMI: 24.3 ± 2.9; VO_2peak: 31.1 ± 8.8 mL/min/kg) were recruited. Participants were tested for their maximal oxygen uptake (VO_2peak) as well as cardiovascular and metabolic risk factors. Venous fasting blood samples were collected. For further analysis, MR_PBMC was measured using the Oroboros O2k-Oxygraph. T cell subsets were analyzed by flow cytometry, serum cytokines by LUMINEX assays, and gene expression by qPCR analysis. We found positive associations between basal and maximal MR_PBMC, and the percentage of CD4⁺ T cells, with a notable link to naïve CD4⁺ T cells (p < 0.05). Maximal MR_PBMC was negatively associated with proportion of effector memory CD4⁺ T cells (p < 0.05). Basal MR_PBMC showed negative associations with pro-inflammatory serum cytokine tumor necrosis factor alpha (TNF-α), while maximal MR_PBMC was positively associated with interleukin 8 (IL-8), intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor (VEGF) (p < 0.05). Intracellular signaling markers, including mRNA level of signal transducer and activator of transcription 3 (STAT3), also showed positive associations with maximal MR_PBMC (p < 0.05). No correlations were found for variables such as cardiorespiratory fitness, IL-6, and IL-10. In conclusion, PBMC mitochondrial bioenergetics are linked to T cell subpopulations and systemic inflammation in healthy older adults. Higher mitochondrial respiration reflecting better mitochondrial function favors a more naïve CD4⁺ T cell distribution. In contrast, lower mitochondrial function was observed in individuals with a more pro-inflammatory profile, suggesting a potential relationship between immune status and mitochondrial bioenergetics in older adults.

Cancer is a leading cause of death in developed countries, despite many breakthroughs in targeted small molecule and immunotherapeutic interventions. A deeper understanding of the characteristics and processes that underlie malignancy will enable us to develop more effective therapeutic options to improve patient outcomes. One particular area of interest is in cancer cell metabolism. Even as early as the 1920s, Otto Warburg recognized dysregulated metabolism in cancerous cells. Altered metabolism may provide targetable nutrient dependencies for further clinical development, either by nutrient restriction or pathway inhibition. More recently, researchers have observed an increasingly strong linkage between altered mitochondrial Ca²⁺ homeostasis and tumor cell metabolism, with strong implications for therapeutic targeting. In this review, we summarize the literature surrounding mitochondrial Ca²⁺ homeostasis, metabolism, and cancer, as well as providing a discussion of the potential for mitochondrial Ca²⁺ modulation as an anticancer therapeutic modality.

K_Ca3.1 ion channel is a calcium-activated potassium channel expressed in various tissues, showing dual localization to the plasma membrane and to mitochondria. This channel is highly expressed in numerous cancers and has been implicated in the regulation of proliferation and migration. The molecular details of the signaling pathways linked to regulation exerted by K_Ca3.1 in cancer cells are, however, not fully elucidated yet. Therefore, we determined the interactome of K_Ca3.1 using proximity labeling in intact KPC pancreatic cancer cells that mirror the aggressive metastatic behavior of human pancreatic cancer. The results highlight several novel interactors, including those residing in intracellular membranes. The K_Ca3.1 channel proxisome and related pathways are discussed in light of our current knowledge about K_Ca3.1 and pancreatic cancer, available in public databases.