Reduced mitochondrial activity in colonocytes facilitates AMPKα2-dependent inflammation.
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 cytochromecoxidase I/IV and lower ATP levels. Thus, we generated colonic ρ0cells 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 ρ0cells augmented IL-8 expression by 9-fold (P< 0.01)viaNF-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.
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Sandra
S
Heller
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Harrison M
HM
Penrose
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Chloe
C
Cable
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Debjani
D
Biswas
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Hani
H
Nakhoul
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Melody
M
Baddoo
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA.
Erik
E
Flemington
Department of Surgery, NorthShore Research Institute, University of Chicago Pritzker School of Medicine, Evanston, Illinois, USA.
Susan E
SE
Crawford
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, Louisiana, USA; ssavkovi@tulane.edu.
Suzana D
SD
Savkovic
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C534978:Prkaa2 protein, mouse; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases
RNA-seq; inflammatory bowel disease; intestine; ρ0 cells