TGF-beta signaling in mitochondrial dynamics

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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.