Cisd2 Deficiency Impairs Neutrophil Function by Regulating Calcium Homeostasis via Calnexin and SERCA

Our study investigated the role of Cisd2, a gene associated with Wolfram syndrome and premature aging, in the context of immunosenescence. We used Cisd2 knockout (KO) mice as a model and observed that these mice had a shorter lifespan and early onset of aging-related features, including hair loss. Notably, these mice had an increased number of neutrophils in their blood, but these neutrophils were functionally impaired. Through mass spectrometry, we discovered that Cisd2 interacts with Calnexin, which is involved in protein quality control and calcium homeostasis by interacting with the sarcoendoplasmic reticulum calcium transport ATPase (SERCA). Our findings suggest that Cisd2 deficiency impairs neutrophil function by disrupting calcium homeostasis through its interaction with Calnexin and SERCA.