Changes in mitochondrial DNA that increase levels of ATP in the intestinal mucosa protect mice from colitis, according to the November issue of Gastroenterology. Strategies to increase mitochondrial ATP production by intestinal epithelial cells might therefore be developed to treat patients with ulcerative colitis (UC).
Characteristics of UC include reduced levels of ATP and disrupted energy homeostasis in the intestinal mucosa. Intestinal tissues from patients have also been shown to have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex—mitochondrial dysfunction could contribute to the pathogenesis of this inflammatory disorder.
Florian Bär et al. performed studies in conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex during development of colitis.
They found that mice with increased activity of the mucosal OXPHOS complex and levels of ATP (BL6.NOD and BL6.NZB mice) developed less-severe colitis after administration of dextran sodium sulfate (DSS) or trinitrobenzene sulfonate (TNBS) than mice with lower mucosal levels of ATP (BL6.BL6 and BL6.AKR mice). The BL6.NOD and BL6.NZB mice have a polymorphism in the mt-tRNAArg gene that affects tRNA function and mitochondrial biogenesis, leading to increased levels of ATP in mucosal cells.
BL6.NOD and BL6.NZB mice were almost completely protected from DSS-induced colitis, with significantly reduced disease activity index scores and smaller reductions in colon length, compared with BL6.BL6 and BL6.AKR mice. BL6.NOD and BL6.NZB mice also developed significantly less TNBS-induced colitis, with reduced weight loss and only mild endoscopic and histopathologic inflammatory changes, compared with BL6.BL6 and BL6.AKR mice.
How could the mitochondria protect against colitis? Bär et al. propose that the mitochondria mediate the epithelial regenerative potential, involving a careful balance between cell proliferation and apoptosis. These mechanisms depend on cellular energy supply and could therefore be affected by variants in mitochondrial DNA.
The authors observed significantly increased proliferation of enterocytes from BL6.NOD and BL6.NZB mice, compared with the other strains. Colon tissues from these mice also had increased activity of the transcription factor NFkB, which regulates mucosal homeostasis and epithelial cell proliferation.
In an editorial that accompanies the article, David L. Boone and Mike A. Teitell explain that mitochondria are platforms for innate immune signaling, including responses to viruses and for activation of the NLRP3 inflammasome. Further exploration of the link between variants in mtDNA, NFkB activity, intestinal cell proliferation, and protection from colitis could increase our understanding the pathogenesis of IBD.