Mcl-1 promotes pluripotency in human embryonic stem cells (hESCs) through modulation of mitochondrial dynamics
Human embryonic stem cells (hESCs) are characterized by their key properties of self-renewal, pluripotency, and the ability to differentiate into any cell type. It has recently been proposed that mitochondrial organization and metabolic demands of hESCs may assist in governing these properties. Preliminary data from our lab show that Myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic Bcl-2 family protein associates with key mitochondrial dynamics proteins, Opa1 (Optic atrophy type 1) and Drp-1 (Dynamin-related protein 1). These proteins facilitate mitochondrial fusion and fission (fragmentation), respectively. Mcl-1 is highly expressed in hESCs and decreases quickly upon differentiation, suggesting that it may play a role in stem cell pluripotent maintenance. My project aims to define the changes that occur in mitochondrial morphology, apoptotic machinery, and pluripotency marker expression when Mcl-1 is inhibited or depleted in hESCs. I will study this through both small molecule inhibition and siRNA knockdown of Mcl-1, followed by analysis of protein levels and mitochondrial morphology through Western blotting and immunofluorescence (IF). These studies will elucidate the novel role of Mcl-1 in the regulation of mitochondrial dynamics, which could provide better models for human mitochondrial diseases by furthering our understanding of molecular mechanisms that underlie stem cell differentiation.