Intestinal
inflammation is associated with low levels of mucosal
ATP, highlighting the importance of mitochondrial function associated with
ATP production in the pathophysiology of the disease. In the inflamed colon of humans and mice, we found decreased levels of mitochondrial complex
cytochrome c oxidase I/IV and lower
ATP levels. Thus, we generated colonic ρ0 cells with reduced mitochondrial function linked to
ATP production by selective depletion of
mitochondrial DNA. In these cells,
RNA sequencing revealed a substantial number of differentially expressed transcripts, among which 240 belonged to inflammatory pathways activated in human inflamed colon and TNF-α-treated cells (false discovery rate < 0.05). TNF-α treatment of colonic ρ0 cells augmented
IL-8 expression by 9-fold (P < 0.01) via NF-κB compared to TNF-α-treated control. Moreover, reduced mitochondrial function facilitated TNF-α-mediated NF-κB
luciferase promoter activity as a result of lowered inhibitory IκBα (nuclear factor of κ light
polypeptide gene enhancer in B-cell inhibitor, α), leading to elevated NF-κB. In cells with reduced mitochondrial function, TNF-α facilitated AMPKα2 activation by 8-fold (P < 0.01), which was involved in NF-κB-dependent
IL-8 expression. Last, in human and mouse colon, anti-TNF-α treatment restored reduced mitochondria-dependent
inflammation. We propose that selective targeting of this novel mechanism provides new treatment opportunities for intestinal
inflammation.-Heller, S., Penrose, H. M., Cable, C., Biswas, D., Nakhoul, H., Baddoo, M., Flemington, E., Crawford, S. E., Savkovic, S. D. Reduced mitochondrial activity in colonocytes facilitates AMPKα2-dependent
inflammation.