Mitochondrial Ca2+ in B cell signaling and metabolism

B 细胞信号传导和代谢中的线粒体 Ca2

• 批准号: 528175517
• 负责人: Professorin Dr. Julia Jellusova
• 金额: --
• 依托单位: Institut für Klinische Chemie und Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/528175517?language=en
• 关键词: Mitochondrial; Ca2+; cell; signaling; metabolism

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.

钙（Ca 2+）是一种多功能的第二信使，已知其控制对B细胞命运决定至关重要的各种细胞内信号传导途径。此外，Ca 2+也是细胞凋亡诱导中的效应分子，并通过增强几种代谢酶的活性在细胞生物能量学中发挥作用。在静息B细胞中，Ca 2+被隔离在内质网（ER）中，并且在B细胞受体刺激后迅速进入胞质溶胶以激活Ca 2+依赖性信号转导。ER可以通过专门的接触位点与线粒体相互作用，并交换包括Ca 2+在内的小分子。线粒体含有大量的Ca 2+，但线粒体Ca 2+在B细胞中的确切作用目前知之甚少。在我们的初步结果中，我们发现ER-线粒体接触位点的形成和线粒体钙摄取受细胞活化以及代谢和ER应激的控制。反过来，我们发现线粒体Ca 2+水平的变化影响B细胞信号传导、线粒体活性、增殖和存活。我们现在的目标是确定响应刺激和应激的ER-线粒体相互作用和线粒体Ca 2+稳态的信号分子。此外，我们试图剖析线粒体Ca 2+依赖性调节B细胞功能的分子机制。鉴于Ca 2+在B细胞中发挥的多方面作用，更好地理解线粒体Ca 2+调节提供了在未来鉴定用于治疗B细胞衍生疾病的新靶点的可能性。