Pantoja Newman Patricia da Silva, Bajwa Amandeep, De Mario Agnese, Mammucari Cristina, Mancarella Salvatore
Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States.
Department of Surgery, Transplant Research Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States.
Am J Physiol Cell Physiol. 2025 Jun 1;328(6):C1880-C1892. doi: 10.1152/ajpcell.00822.2024. Epub 2025 Apr 29.
Cardiac fibroblasts (CFs) play a crucial role in regulating normal heart function and are also involved in the pathological remodeling of the heart that occurs due to hypertension, myocardial infarction, and heart failure. Metabolic changes in fibroblasts are key drivers in the progression of these diseases. Calcium (Ca) signaling and Ca ion channels control many functions of fibroblasts. Orai Ca channels are abundantly expressed in fibroblasts; however, their exact role is not yet fully understood. This study examined the role of Orai Ca channels in maintaining Ca homeostasis within organelles and in energy production in CFs. We found that chronic inhibition of Orai activity altered the expression levels of major metabolic enzymes, affecting the overall cell metabolism. Orai channels are required to refill the endoplasmic reticulum (ER) store. Acute Orai channel activity inhibition reduced Ca content in the ER and mitochondria and was associated with the impaired ability to use glucose as a primary energy source. These results have significant implications for understanding the role of Orai-dependent Ca entry in maintaining organellar Ca homeostasis and cellular metabolic flexibility, sparking further research in this area. We show that Orai actively contributes to organellar Ca concentration and energy homeostasis of the cardiac fibroblast. These findings can have a significant impact during fibrogenesis.
心脏成纤维细胞（CFs）在调节正常心脏功能中起关键作用，并且也参与因高血压、心肌梗死和心力衰竭而发生的心脏病理重塑。成纤维细胞的代谢变化是这些疾病进展的关键驱动因素。钙（Ca）信号传导和钙离子通道控制着成纤维细胞的许多功能。Orai钙通道在成纤维细胞中大量表达；然而，它们的确切作用尚未完全了解。本研究探讨了Orai钙通道在维持细胞器内钙稳态以及心脏成纤维细胞能量产生中的作用。我们发现，长期抑制Orai活性会改变主要代谢酶的表达水平，影响整体细胞代谢。Orai通道是内质网（ER）钙库重新充盈所必需的。急性抑制Orai通道活性会降低内质网和线粒体中的钙含量，并与利用葡萄糖作为主要能量来源的能力受损有关。这些结果对于理解依赖Orai的钙内流在维持细胞器钙稳态和细胞代谢灵活性中的作用具有重要意义，引发了该领域的进一步研究。我们表明，Orai积极参与心脏成纤维细胞的细胞器钙浓度和能量稳态。这些发现可能在纤维化形成过程中产生重大影响。
