Orai channel pharmacological manipulation reduces metabolic flexibility in cardiac fibroblasts.

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 (Ca²⁺) signaling and Ca²⁺ ion channels control many functions of fibroblasts. Orai Ca²⁺ channels are abundantly expressed in fibroblasts; however, their exact role is not yet fully understood. This study examined the role of Orai Ca²⁺ channels in maintaining Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ entry in maintaining organellar Ca²⁺ homeostasis and cellular metabolic flexibility, sparking further research in this area.NEW & NOTEWORTHY We show that Orai actively contributes to organellar Ca²⁺ concentration and energy homeostasis of the cardiac fibroblast. These findings can have a significant impact during fibrogenesis.