Role of Altered Mitochondrial dynamics in Graft Versus Host Disease - Project Summary : Graft-versus-host disease (GVHD) is the leading cause of non-relapse mortality following hematopoietic stem cell transplantation (HSCT). The severity of GVHD has been linked to the release of damage associated molecular patterns (DAMPs) in response to cytotoxic pre-HSCT conditioning mediated tissue injury. Recently, we have shown that the conditioning mediated release of damaged mitochondria (exMito) directly contributes to the initiation of GVHD. In this proposal, we will identify the mechanistic pathways leading to generation and release of dysfunctional mitochondria during pre-HSCT conditioning in order to discover new therapeutic targets to prevent GVHD. We have found that cytotoxic pre-HSCT conditioning leads to excessive mitochondrial fission independent of mitochondrial autophagy (mitophagy), creating an imbalance in mitochondrial dynamics which results in extracellular release of dysfunctional mitochondria. Using mouse models, we found that exposure of host immune cells to these released mitochondria during HSCT accelerated the onset and severity of acute GVHD. Importantly, our preliminary data demonstrates that correcting mitochondrial dynamics by decreasing mitochondrial fission and inducing mitophagy prevents extracellular release of damaged mitochondria following conditioning. Our overall hypothesis is that correcting impairments in mitochondrial dynamics will decrease exMito release following conditioning and prevent GVHD without impairing donor HSC function. To test this hypothesis, we will first determine the downstream mechanisms which link excessive mitochondrial fission to exMito release, host APC activation, and incidence of GVHD. Second, we will determine how impairments in mitophagy impact conditioning-mediated exMito release and incidence of GVHD. Finally, we will determine the impact of targeting mitochondrial dynamics on donor HSC function following transplant. This project addresses a major clinical barrier for HSCT by identifying targetable mechanisms that mediate the initiation of GVHD and testing novel biologically driven therapeutic candidates. Specifically, we will: 1) define novel mechanisms that mediate impairments in mitochondrial dynamics and extracellular mitochondrial content secondary to conditioning, 2) apply single cell approaches to characterize how impairments in mitochondrial dynamics impact the immune cell response following conditioning for HSCT, and 3) determine the impact of altered mitochondrial dynamics on HSC function following transplant. Altogether, this will provide the foundation for a new class of therapeutics beneficial for prevention of GVHD and other inflammatory disorders.
