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Mitochondrial complex I dysfunction alters the balance of soluble and membrane-bound TNF during chronic experimental
Ainize Peña-Cearra1,2, Miguel Angel Pascual-Itoiz1, Jose Luis Lavín1,3
1CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, Building 801A, 48160, Derio, Spain.
Abstract:
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.
Insights
Mitochondrial protein MCJ deficiency unexpectedly reduces inflammatory bowel disease severity in chronic models by altering microbial composition and increasing TACE activity. This suggests MCJ influences gut inflammation adaptation.
Area of Science:
- Immunology
- Gastroenterology
- Mitochondrial Biology
Background:
- Inflammatory bowel disease (IBD) is a complex chronic condition influenced by genetic, environmental, microbial, and immune factors.
- MCJ is a mitochondrial protein regulating macrophage metabolism and bacterial response.
- Previous studies indicated MCJ deficiency exacerbates acute DSS-induced colitis.
Purpose of the Study:
- To investigate the role of MCJ in chronic inflammatory bowel disease models.
- To explore the impact of MCJ deficiency on TACE activity and microbial composition during chronic inflammation.
Main Methods:
- Utilized a chronic murine model of DSS-induced colitis.
- Assessed TACE activity in MCJ-deficient mice.
- Analyzed gut microbial composition and diversity using sequencing.
Main Results:
- MCJ-deficient mice exhibited augmented TACE activity in chronic inflammation.
- This TACE activity correlated with a milder disease phenotype and increased soluble TNF.
- MCJ deficiency led to increased gut microbial alpha diversity and reduced Ruminococcus gnavus.
Conclusions:
- MCJ plays a role in the dynamic metabolic adaptation of colon tissue to chronic inflammation.
- MCJ deficiency can lead to beneficial changes in microbial composition and TACE activity, potentially mitigating chronic IBD.
- Mitochondrial function is a key regulator of the host-microbe-inflammation axis in IBD.
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