Mitochondrial Ca2+ in B cell signaling and metabolism

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Calcium (Ca2+) is a versatile second messenger known to govern various intracellular signaling pathways central to B cell fate decisions. Additionally, Ca2+ is also an effector molecule in apoptosis induction and plays a role in cellular bioenergetics by enhancing the activity of several metabolic enzymes. In resting B cells, Ca2+ is sequestered in the endoplasmic reticulum (ER) and enters the cytosol quickly after B cell receptor stimulation to activate Ca2+ dependent signal transduction. The ER can interact with the mitochondria through dedicated contact sites and exchange small molecules including Ca2+. Mitochondria harbour significant amounts of Ca2+, yet the exact role of mitochondrial Ca2+ in B cells is currently poorly understood. In our preliminary results we have found that the formation of ER-mitochondria contact sites and mitochondrial calcium uptake are governed by cellular activation as well as metabolic and ER stress. In turn, we have found changes in mitochondrial Ca2+ levels to affect B cell signaling, mitochondrial activity, proliferation and survival. Our goal now is to identify signaling molecules orchestrating ER-mitochondria interactions and mitochondrial Ca2+ homeostasis in response to stimulation and stress. Moreover, we seek to dissect the molecular mechanisms of mitochondrial Ca2+ -dependent regulation of B cell function. Given the versatile role Ca2+ plays in B cells, a better understanding of mitochondrial Ca2+ regulation offers the possibility to identify new targets for treatment of B cell derived disorders in the future.