Mitochondrial complex I dysfunction alters the balance of soluble and membrane-bound TNF during chronic experimental colitis

• Published in: Scientific reports Vol. 12; no. 1; p. 9977
• Main Authors: Peña-Cearra, Ainize, Pascual-Itoiz, Miguel Angel, Lavín, Jose Luis, Fuertes, Miguel, Martín-Ruiz, Itziar, Castelo, Janire, Palacios, Ainhoa, Barriales, Diego, Fullaondo, Asier, Aransay, Ana M, Rodríguez, Hector, Anguita, Juan, Abecia, Leticia
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15.06.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animal models; Colitis; Electron transport chain; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Macrophages; Metabolism; Mitochondria; NADH-ubiquinone oxidoreductase; Phenotypes; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-13480-y

Inflammatory bowel disease (IBD) is a complex, chronic, relapsing and heterogeneous disease induced by environmental, genomic, microbial and immunological factors. MCJ is a mitochondrial protein that regulates the metabolic status of macrophages and their response to translocated bacteria. Previously, an acute murine model of DSS-induced colitis showed increased disease severity due to MCJ deficiency. Unexpectedly, we now show that MCJ-deficient mice have augmented tumor necrosis factor α converting enzyme (TACE) activity in the context of chronic inflammation. This adaptative change likely affects the balance between soluble and transmembrane TNF and supports the association of the soluble form and a milder phenotype. Interestingly, the general shifts in microbial composition previously observed during acute inflammation were absent in the chronic model of inflammation in MCJ-deficient mice. However, the lack of the mitochondrial protein resulted in increased alpha diversity and the reduction in critical microbial members associated with inflammation, such as Ruminococcus gnavus, which could be associated with TACE activity. These results provide evidence of the dynamic metabolic adaptation of the colon tissue to chronic inflammatory changes mediated by the control of mitochondrial function.