The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis

Autor: Ainhoa Palacios, Rebeca Martín, Aize Pellon, Virginia García-Cañas, Ana Mª Aransay, Rafael Prados-Rosales, Leticia Abecia, Carolina Simó, Ana Carreras-González, Juan Anguita, Estíbaliz Atondo, Héctor Rodríguez, Diego Barriales, Juana M. Flores, Ainize Peña-Cearra, Miguel Angel Pascual-Itoiz, Itziar Martín-Ruiz, Asier Fullaondo, Julen Tomás-Cortázar, José Luis Lavín
Přispěvatelé: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), European Commission, Eusko Jaurlaritza, Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa, Universidad del País Vasco
Rok vydání: 2019
Předmět:
0301 basic medicine
lcsh:Medicine
Mitochondrion
Biology
ADAM17 Protein
Severity of Illness Index
Article
Proinflammatory cytokine
Mitochondrial Proteins
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
Gene expression
medicine
Animals
Humans
Colitis
lcsh:Science
Inner mitochondrial membrane
Acute inflammation
Phylogeny
Regulation of gene expression
Tissue Inhibitor of Metalloproteinase-3
Multidisciplinary
Bacteria
Tumor Necrosis Factor-alpha
Microbiota
lcsh:R
Respiratory chain complex
HSP40 Heat-Shock Proteins
medicine.disease
Disease Models
Animal
030104 developmental biology
Gene Expression Regulation
Ulcerative colitis
Receptors
Tumor Necrosis Factor
Type I
Immunology
Dysbiosis
lcsh:Q
030211 gastroenterology & hepatology
Colitis
Ulcerative
Gene Deletion
Molecular Chaperones
Zdroj: Scientific Reports
Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 2045-2322
Popis: Recent evidences indicate that mitochondrial genes and function are decreased in active ulcerative colitis (UC) patients, in particular, the activity of Complex I of the electron transport chain is heavily compromised. MCJ is a mitochondrial inner membrane protein identified as a natural inhibitor of respiratory chain Complex I. The induction of experimental colitis in MCJ-deficient mice leads to the upregulation of Timp3 expression resulting in the inhibition of TACE activity that likely inhibits Tnf and Tnfr1 shedding from the cell membrane in the colon. MCJ-deficient mice also show higher expression of Myd88 and Tlr9, proinflammatory genes and disease severity. Interestingly, the absence of MCJ resulted in distinct microbiota metabolism and composition, including a member of the gut community in UC patients, Ruminococcus gnavus. These changes provoked an effect on IgA levels. Gene expression analyses in UC patients showed decreased levels of MCJ and higher expression of TIMP3, suggesting a relevant role of mitochondrial genes and function among active UC. The MCJ deficiency disturbs the regulatory relationship between the host mitochondria and microbiota affecting disease severity. Our results indicate that mitochondria function may be an important factor in the pathogenesis. All together support the importance of MCJ regulation during UC.
This work was supported by grants [AGL2017-86757-R to LA, SAF2015-65327-R to JA, AGL2017-89055-R to CS and VGC, SAF2016-77433-R to RPR] from the Spanish Ministry of Economy and Competitiveness co financed with FEDER funds, the XIII Grant from GETECCU-Otsuka (Grupo Español de Trabajo en Enfermedad de Crohn y Colitis ulcerosa to LA) and Basque Government project for health [number 2015111117 to LA]. LA and RP-R are Ramón y Cajal fellows [RYC-2013-13666] from the Spanish Ministry of Economy and Competitiveness. RP-R is supported in part by National Institute of Health [grant AI115091]. APC is a fellow of the University of the Basque Country (UPV/EHU), DB from FPI program of the Spanish Ministry of Economy and Competitiveness, and AC and AP from the Basque Government. CIC bioGUNE support was provided by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek Programs), the Innovation Technology Department of Bizkaia County, and Spanish MINECO the Severo Ochoa Excellence Accreditation [SEV-2016-0644].
Databáze: OpenAIRE
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