Dissecting the role of mitochondrial gene polymorphism and function in human and murine intestinal inflammation.

• Applicant: Professor Dr. Christian Sina
• Subject Area: Gastroenterology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314505160

Ulcerative Colitis (UC) belongs to the group of inflammatory bowel diseases and is characterized by chronic mucosal inflammation of the large bowel based on impaired intestinal barrier function. An imbalance in intestinal energy homeostasis acts as an underlying pathologic mechanism for UC. This has been suggested for many years based on the observation that mitochondrial oxidative phosphorylation (OXPHOS) activity is impaired in the colon of UC patients. Considering mitochondria being the major energy source of cellular energy production this observation let to the hypothesis that mitochondrial dysfunction may be a pathogenetic factor driving mucosal energy depletion in UC. Energy supply occurs along a metabolic trajectory in the intestinal epithelium. It was demonstrated that only terminally differentiated cells at the upper third of the intestinal crypt exert relevant OXPHOS activity. Among these cells goblet cells display highest OXPHOS activity. Main functions of goblet cells that are highly energy dependent comprise mucus production and secretion as a crucial part of the intestinal barrier. Here we propose that impaired OXPHOS activity in goblet cells results in intestinal barrier dysfunction and in particular mucus depletion, which is a pathophysiological hallmark in UC.However, due to the lack of appropriate animal models, the influence of mitochondrial OXPHOS function on intestinal barrier integrity with special emphasis on colitis development was never sufficiently tested in vivo. This situation has recently changed with the introduction of conplastic inbred mice strains (CIS) that encode well defined and natural occurring gene polymorphisms in their mitochondrial but not nuclear genomes. Notably, these mice display either enhanced or reduced strain specific mucosal OXPHOS activities and ATP levels. Therefore, they are a unique tool to delineate the influence of mitochondrial respiration on intestinal barrier function and mucosal inflammation.In accordance with our hypothesis, we found CIS mice with altered OXPHOS activity and reduced mucosal ATP level to be highly susceptible to experimental colitis models. Moreover, these mice displayed a thinner intestinal mucus layer and had significant alterations in their gut microbiota. Vice versa, CIS mice with increased mucosal ATP level were found to be protected against experimental colitis. Here, we aim to perform in vivo, ex vivo as well as in vitro in-depth analyses of molecular mechanisms and consequences of impaired OXPHOS activity on intestinal barrier function in mice and humans. Moreover, we will focus on mitochondrial heteroplasmy and dynamics as potential determinants for mitochondrial dysfunction in UC.We expect to get further insights into the pathophysiological role of mitochondrial gene variations and impaired mitochondrial respiration in the context of intestinal barrier function and mucosal inflammation in order to further elucidate the pathogenesis of UC.

• DFG Programme: Research Grants