TGF-beta signaling in mitochondrial dynamics

摘要 转化生长因子-β几乎影响哺乳动物生理的方方面面，从早期胚胎发育到成年。 通过调节不同的细胞功能，包括增殖、分化和 细胞凋亡。转化生长因子-β信号在细胞新陈代谢中也发挥着重要作用，尽管 了解其对线粒体生物发生、呼吸和细胞器的差异调控的研究进展 毁灭。虽然这种不同的影响被理论认为主要是通过慢作用的上下文基因发生的 在调控方面，转化生长因子-β也能够诱导更快速、直接和可逆的线粒体形状变化 并通过基本未知的机制−发挥作用，这是一个代表重要知识差距的关键方面 在战场上。我们的研究计划集中在两个强有力的对立机制上，通过这两个主要机制 转化生长因子-β效应器，Smad2和Tak1，控制线粒体融合/分裂动力学实现和维持 代谢动态平衡。我们试图了解管理它们的组织、激活和 线粒体重塑的调控及其如何通过血管生成影响细胞行为 发展模式体系。我们的研究将为复杂的转化生长因子-β信号转导机制提供独特的视角 网络控制线粒体的动态，影响它们在体内的代谢、发育和内环境平衡作用 血管生理学。

ABSTRACT TGF-β affects virtually all aspects of mammalian physiology starting from early embryonic development to adult tissue homeostasis through regulation of diverse cellular functions including proliferation, differentiation, and apoptosis. TGF-β signaling also plays an important role in cell metabolism, although there has been incremental progress in understanding how it differentially regulates mitochondrial biogenesis, respiration, and organelle destruction. While such varying effects are theorized to occur primarily through slow-acting contextual gene regulation, TGF-β is also capable of inducing more rapid, direct, and reversible changes in mitochondrial shape and function through largely unknown mechanisms− a key aspect that represents an important knowledge gap in the field. Our research program has focused on two powerfully opposing mechanisms by which two major TGF-β effectors, Smad2 and TAK1, control mitochondrial fusion/fission dynamics to achieve and maintain metabolic homeostasis. We seek to understand mechanisms governing their organization, activation, and regulation in mitochondrial remodeling and how they influence cell behavior using angiogenesis as a developmental model system. Our studies will provide unique perspectives on how the complex TGF-β signaling networks control mitochondrial dynamics to affect their metabolic, developmental and homeostatic roles in vascular physiology.