KU Clinical Research: Fairway Auditorium
4350 Shawnee Mission Parkway Fairway, KS 66205
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Molecular Regulation of Energy Metabolism During Early Mammalian Development: Conserved Transcription Factor TEAD4 Controls Mitochondrial Transcription
Early mammalian development is critically dependent on the establishment of oxidative energy metabolism within the trophectoderm (TE) lineage. Unlike inner cell mass (ICM), TE cells enhance ATP production via mitochondrial oxidative phosphorylation (OXPHOS) and this metabolic preference is essential for blastocyst maturation. However, molecular mechanisms that regulate establishment of oxidative energy metabolism in TE cells are incompletely understood. Here, we show that conserved transcription factor TEAD4, which is essential for pre-implantation mammalian development, regulates this process by promoting mitochondrial transcription. In the developing TE and TE-derived trophoblast stem cells (TSCs), TEAD4 localizes to mitochondria, binds to mitochondrial DNA (mtDNA) and facilitates mtDNA transcription by recruiting mitochondrial RNA Polymerase (POLRMT). Loss of TEAD4 impairs recruitment of POLRMT, resulting in reduced expression of mtDNA-encoded electron transport chain components, thereby inhibiting oxidative energy metabolism. Our studies identify a novel TEAD4-dependent molecular mechanism that regulates energy metabolism in the TE lineage to ensure mammalian development.
Speaker- Soumen Paul, PhD
Dr. Paul is an Associate Professor at the Department of Pathology & Laboratory Medicine of the University of Kansas Medical Center. He has a broad knowledge in stem cell biology, with specific expertise in trophoblast stem cells. A major research effort in his laboratory is focused to delineate transcriptional mechanisms that regulate the genesis of Trophectoderm during early embryonic development, as well as understanding molecular mechanisms controlling self-renewal, differentiation, and function of trophoblast stem/progenitors cells in rodents and human. In recent years, Dr. Paul published multiple manuscripts studying transcriptional mechanisms in to understand molecular mechanisms that control establishment of the trophoblast lineage. In addition, his laboratory made fundamental discoveries that control embryonic stem cell pluripotency and vascular and hematopoietic development.
Innovative Approaches for the Identification of Mitochondrial Signaling Networks
Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response, and epigenetic regulation of gene expression. Mitochondria play a central role in these pathways, not only through energetics and ATP production, but also through activities of metabolites generated in the tricarboxylic acid (TCA) cycle, and mitochondrial-nuclear signaling related to mitochondrial morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Emerging evidence suggests that both endogenous and exogenous stressors can induce altered epigenetic patterns including histone modifications and altered DNA methylation of nuclear-encoded genes, possibly through mitochondria-mediated responses to changes in energetics and/or ROS signaling. A deeper understanding of the signaling (cross-talk) between the mitochondria and the nucleus or other cellular response pathways will lead to a more comprehensive understanding of how cells sense and respond to both internal and external stress. Our current studies explores the signaling cross-talk between the mitochondria and other cellular components through two specific approaches that are unique to the mitochondria; a) mitochondrial membrane transport, an essential component of this membrane bound organelle, and 2) mitochondrial oxidative stress, an integral part of mitochondrial respiration essential for overall cellular bioenergetics.
Speaker- Partha Kasturi, PhD
Dr. Kasturi is an Associate Professor of Pharmacology, Toxicology and Therapeutics at the University of Kansas Medical Center. The overall research interest of his laboratory is to define the physiological and molecular mechanisms that link mitochondrial function to cellular homeostasis, with an emphasis on understanding the degree of molecular defects, and the consequences of such molecular defects to systemic homeostasis. Dr. Kasturi’s laboratory explores this broad scientific interest with two specific approaches that are unique to mitochondria; 1) mitochondrial membrane transport, an essential component of this membrane bound organelle, and 2) mitochondrial oxidative stress, an integral part of mitochondrial respiration essential for overall cellular bioenergetics.