Mitonuclear Communication During the Pathogenesis of Inflammatory Bowel Disease

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

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Abstract

Project Summary/Abstract: There is increasing appreciation for mitochondrial dysfunction as both a cause of and therapeutic target for inflammatory bowel disease (IBD). The broad goal of this proposal is to determine how abnormal mitochondrial dynamics and function within the intestinal epithelium contribute to IBD pathogenesis and whether reversing or preventing dysfunction can improve clinical outcomes. Mitochondrial homeostasis is maintained via mitochondrial biogenesis and the coordinated process of mitochondrial dynamics, including fusion, fission and mitophagy, working in concert to balance energy metabolism and regulate mitochondrial structure and function. We previously demonstrated that downregulation of PGC1α in the intestinal epithelium of patients with ulcerative colitis (UC) results in a decrease in biogenesis, contributing to a decline in mitochondrial function and the antioxidant response. We and others went on to describe a “mitochondriopathy” of UC, representing the most significant transcriptomic hallmark of treatment-naïve pediatric-onset UC. Despite these findings, several key questions remain. First, the hallmark of this mitochondriopathy is a transcriptional downregulation of PGC1, yet the cause of this downregulation remains unknown. We now provide evidence of Parkin-interacting substrate (PARIS)-mediated PGC1α transcriptional inhibition during disease, secondary to a decrease in cellular PARKIN. Second, apart from a decrease in mitochondrial biogenesis, it is not known how PGC1 downregulation directly impacts mitochondrial dynamics. Finally, it is unclear how PGC1-dependent metabolic reprogramming of the intestinal epithelium may impact mucosal healing and the ultimate outcomes of IBD. Our working hypothesis is that the mitochondriopathy of IBD is a signature feature of disease, with important functional consequences, and one that is amenable to therapeutic targeting. In Aim 1, we propose to investigate the PARKIN-PARIS-PGC1α axis using multiple, inducible transgenic mouse strains in models of intestinal injury and repair. In Aim 2, we evaluate the impact of PGC1α downregulation on mitochondrial dynamics during IBD utilizing novel approaches to live-cell imaging of intestinal organoids. Finally, in Aim 3 we will evaluate the impact of PGC1α-driven metabolic flux on pro-inflammatory and pro-fibrotic pathways in UC using human intestinal organoids (HIOs) induced from pluripotent stem cells (iPSCs), potentially outlining a novel mechanism for an understudied and devastating complication of chronic disease. Targeting the epithelial mitochondriopathy of IBD could offer the opportunity to minimize the epithelial impact of disease, improving mucosal healing while still mitigating the robust immune response in patients with immune-mediated therapeutics.