Mitochondrial dysfunction in inflammatory bowel disease

Elizabeth A Novak, Kevin P Mollen, Elizabeth A Novak, Kevin P Mollen

Abstract

Inflammatory Bowel Disease (IBD) represents a group of idiopathic disorders characterized by chronic or recurring inflammation of the gastrointestinal tract. While the exact etiology of disease is unknown, IBD is recognized to be a complex, multifactorial disease that results from an intricate interplay of genetic predisposition, an altered immune response, changes in the intestinal microbiota, and environmental factors. Together, these contribute to a destruction of the intestinal epithelial barrier, increased gut permeability, and an influx of immune cells. Given that most cellular functions as well as maintenance of the epithelial barrier is energy-dependent, it is logical to assume that mitochondrial dysfunction may play a key role in both the onset and recurrence of disease. Indeed several studies have demonstrated evidence of mitochondrial stress and alterations in mitochondrial function within the intestinal epithelium of patients with IBD and mice undergoing experimental colitis. Although the hallmarks of mitochondrial dysfunction, including oxidative stress and impaired ATP production are known to be evident in the intestines of patients with IBD, it is as yet unclear whether these processes occur as a cause of consequence of disease. We provide a current review of mitochondrial function in the setting of intestinal inflammation during IBD.

Keywords: autophagy; gut-barrier function; inflammasome; inflammatory bowel disease; intestinal inflammation; metabolic stress; mitochondrial dysfunction; reactive oxygen species.

Figures

Figure 1
Figure 1
IEC function and intestinal homeostasis can be influenced by mitochondrial dysfunction. (A) During intestinal homeostasis, goblet cells produce a healthy mucus layer that protects the IECs from the contents of the lumen, and Paneth cells produce and release antimicrobial peptides to protect IECs. Mitochondria are dense and contain well-formed cristae. The tight junctions inhibit translocation of luminal antigens across the epithelial barrier. Any basal ROS produced is negated by cellular antioxidants. Leukocytes survey the laminia propria for threats. (B) Studies have shown that during the inflammatory conditions of IBD, the mucus layer is reduced and production of antimicrobial peptides is decreased, exposing the intestinal epithelium to the intestinal microbiota and luminal antigens. Mitochondria are swollen and abnormal, and cristae are irregular, resulting in a reduction in ATP production and an increase in ROS. Cellular antioxidants are also decreased, causing a buildup of cellular ROS. There is an increase in epithelial permeability (both transcellular and paracellular) and translocation of bacteria and luminal antigens. This results in an infiltration of immune cells, which also causes an increase of ROS. Both IL-8 and IL-1B are released by immune cells, and immune cell-bacterial interactions further instigates the release of pro-inflammatory mediators, which can feedback onto the IECs and influence other cellular components of the intestinal epithelium.

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