(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Hematopoietic stem cell (HSC) transplantation (HSCT) after conditioning is widely used in the clinic to treat pathological mutations in the lympho-hematopoietic system. The mechanisms on how the bone marrow (BM) microenvironment (ME) and transplanted HSC interact remains a mystery in biology. Understanding the underpinning mechanisms controlling mesenchymal BM-ME and HSC is arguably a major area of interest to optimize HSCT and generate optimal HSCT protocols that result in complete hematopoietic chimerism in the host with minimal or no myeloablative conditioning therapy. Our published data indicate that mesenchymal-lineage MSC undergo massive damage to their mitochondrial function following irradiation. Donor healthy HSPC transfer functional mitochondria to the stromal ME, thus improving mitochondria activity in recipient MSC. Mitochondrial transfer to the mesenchymal-lineage MSC is cell-contact dependent, positively regulated by mitochondrial connexin-43 (Cx43) and negatively regulated by cytosolic adenosine monophosphate kinase activity. In this proposal, we hypothesize that mitochondrial transfer from HSPC to BM stroma depends on the activity of Cx43 to control mitochondrial dynamics and downstream mitotransfer and is required for hematopoietic recovery during BM regeneration. The goal of this proposal is to identify the mechanisms by which Cx43 controls HSC mitochondrial dynamics and elucidate in detail the cellular and molecular mechanisms of mitochondria transfer from HSPC to BM MSC. We will identify the mechanisms by which Cx43 controls mitotransfer and regeneration and the role of mitochondrial Cx43 functional domains in mitochondrial dynamics, mitotransfer and hematopoietic regeneration. This proposal is the continuation and natural consequence of the NIDDK R01 DK124115 designed to start the exploration of the role of Cx43 as a regulator of hematopoietic metabolism and regeneration.