Investigating the role of mitochondria in Eosinophilic Esophagitis pathogenesis.

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Project Summary Eosinophilic Esophagitis (EoE) is a chronic type of food allergy whose pathobiology remains incompletely understood. Damaging variants in the nuclear gene encoding the mitochondrial protein DHTKD1 have been identified in EoE patients, indicating a potential role for mitochondria in EoE pathobiology. We have previously reported that IL-13 induces autophagy flux as a cytoprotective mechanism in esophageal epithelium exposed to EoE-relevant inflammatory stimuli. To extend these studies, we evaluated the impact of IL-13 upon mitochondria, a well-established cellular target of autophagy. Unexpectedly, we found an increase in mitochondria in esophageal keratinocytes treated with IL-13 rather than the hypothesized decrease. During her rotation in my lab, Ms. Jackson (the current diversity supplement candidate) found that among EoE-relevant cytokines IL-13 uniquely increased mitochondria in esophageal keratinocytes. She further demonstrated that knockdown of the mitochondrial transcription factor TFAM partially restored squamous cell differentiation in IL- 13-treated esophageal organoids. Based upon these findings, we hypothesize that IL-13-mediated alterations in mitochondrial biology contribute to impaired squamous cell differentiation in EoE. These studies will utilize the experimental platforms and approaches developed during the parent R01 to explore this innovative hypothesis. The Specific Aims of the current proposal are: Aim 1. To define the molecular mechanisms through which IL-13 induces increased mitochondrial content in esophageal keratinocytes; and Aim 2. To elucidate the functional role of mitochondria in EoE pathogenesis. Taken together, these studies will provide novel insight into the role of mitochondria in EoE pathogenesis. Restoration of epithelial differentiation may promote epithelial healing and barrier function in EoE patients, thereby limiting further antigen presentation. Thus, findings from this study have potential for translational impact in EoE. The proposed studies will further provide excellent training opportunities for Ms. Jackson as she develops novel conceptual and technical expertise related to mitochondrial biology and formulated her F31 proposal.