ABSTRACT The role of mitochondrial regulation in cell lineage specification and function During cell lineage specification, metabolic reprogramming, together with transcriptional and epigenetic modifications in the progenitor cells are integral parts of cellular adaptations to the cell fate instructive cues. When this process goes awry, developmental defects as well as malignancies will occur. Common in all the cellular systems, mitochondria are bioenergetic, biosynthetic and signaling organelles central to metabolic remodeling. Understanding mechanisms of mitochondrial function during lineage specification will be critical for therapeutic normalization of derailed cellular metabolism and functions in pathogenesis. Though mitochondrial regulation is still unclear, our published and preliminary work revealed critical roles of mitochondrial metabolism and mitochondrial dynamics during cell lineage specification. Furthermore, differentiated cells continue to receive low-level, constitutive signaling in the basal state (“tonic signals”), important for cell survival or functions. Our research suggested that mitochondrial regulation is actively maintained in mature differentiated cells downstream of tonic signals and revealed potential new regulators for this process. The overarching theme of our research is to unravel the diverse mitochondria mediated mechanisms regulating cell lineage differentiation and homeostatic functions. In Project 1, we will use high resolution imaging to characterize distinct mitochondrial morphology, and dynamic events in live cells. Using genetic tools, and an organ culture system to model cell lineage specification, we will decipher the role of mitochondrial dynamics in metabolic remodeling during differentiation. In Project 2, using a sophisticated system of transferring cells into environments with defined levels of tonic signals, we will assess the alterations in mitochondrial dynamics and functions in the presence and absence of tonic signals. Through pharmacological means or genetic modifications such as CRISPR/Ca9 in differentiated cells, we will determine the causal relationship between mitochondrial regulation and maintenance of cellular functions. Upon completion of our work, we will have uncovered the versatile mechanisms by which mitochondria influence lineage specification and homeostatic functions.