Boosting mitochondria activity by silencing MCJ overcomes cholestasis-induced liver injury
Creators
- Iruzubieta, Paula1
- Goikoetxea-Usandizaga, Naroa2
- Barbier-Torres, Lucía3
- Serrano-Maciá, Marina4
- Fernández-Ramos, David5
- Fernández-Tussy, Pablo6
- Gutiérrez-de Juan, Virginia2
- Lachiondo-Ortega, Sofía7
- Simón, Jorge8
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Bravo, Miren8
- Lopitz-Otsoa, Fernando5
- Robles, Mercedes9
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Ferre-Aracil, Carlos10
- Varela-Rey, Marta11
- Elguezabal, Natalia12
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Calleja-Panero, José Luis10
- Lu, Shelly C.13
- Milkiewicz, Małgorzata14
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Anguita, Juan8
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Monte, Maria J.5
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Marin, Jose J. G.15
- López‑Hoyos, Marcos1
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Delgado, Teresa Cardoso8
- Rincòn, Mercedes R.16
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Crespo García, Javier17
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Martínez-Chantar, María Luz5
- Milkiewicz, Piotr18
- 1. Hospital Universitario Marqués de Valdecilla, Santander, Spain
- 2. Basque Research and Technology Alliance (BRTA), Mendaro, Spain
- 3. Cedars-Sinai Medical Center, Los Angeles, United State
- 4. Universidad Miguel Hernández de Elche, Elche, Spain
- 5. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- 6. Yale School of Medicine, New Haven, United States
- 7. Imperial College London, London, United Kingdom
- 8. CIC BioGUNE, Derio, Spain
- 9. Hospital Regional Universitario Carlos Haya, Malaga, Spain
- 10. Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain
- 11. Universidad de Santiago de Compostela, Santiago de Compostela, Spain
- 12. NEIKER, Basque Institute for Agricultural Research and Development, Derio, Spain
- 13. Cedars-Sinai Medical Center, Los Angeles, United States
- 14. Pomeranian Medical University in Szczecin, Szczecin, Poland
- 15. Universidad de Salamanca, Salamanca, Spain
- 16. University of Vermont College of Medicine, Burlington, United States
- 17. Universidad de Cantabria, Facultad de Medicina, Santander, Spain
- 18. Medical University of Warsaw, Warsaw, Poland
Description
Background & Aims: Mitochondria are the major organelles for the formation of reactive oxygen species (ROS) in the cell, and mitochondrial dysfunction has been described as a key factor in the pathogenesis of cholestatic liver disease. The methylation-controlled J-protein (MCJ) is a mitochondrial protein that interacts with and represses the function of complex I of the electron transport chain. The relevance of MCJ in the pathology of cholestasis has not yet been explored. Methods: We studied the relationship between MCJ and cholestasis-induced liver injury in liver biopsies from patients with chronic cholestatic liver diseases, and in livers and primary hepatocytes obtained from WT and MCJ-KO mice. Bile duct ligation (BDL) was used as an animal model of cholestasis, and primary hepatocytes were treated with toxic doses of bile acids. We evaluated the effect of MCJ silencing for the treatment of cholestasis-induced liver injury. Results: Elevated levels of MCJ were detected in the liver tissue of patients with chronic cholestatic liver disease when compared with normal liver tissue. Likewise, in mouse models, the hepatic levels of MCJ were increased. After BDL, MCJ-KO animals showed significantly decreased inflammation and apoptosis. In an in vitro model of bile-acid induced toxicity, we observed that the loss of MCJ protected mouse primary hepatocytes from bile acid-induced mitochondrial ROS overproduction and ATP depletion, enabling higher cell viability. Finally, the in vivo inhibition of the MCJ expression, following BDL, showed reduced liver injury and a mitigation of the main cholestatic characteristics. Conclusions: We demonstrated that MCJ is involved in the progression of cholestatic liver injury, and our results identified MCJ as a potential therapeutic target to mitigate the liver injury caused by cholestasis. Lay summary: In this study, we examine the effect of mitochondrial respiratory chain inhibition by MCJ on bile acid-induced liver toxicity. The loss of MCJ protects hepatocytes against apoptosis, mitochondrial ROS overproduction, and ATP depletion as a result of bile acid toxicity. Our results identify MCJ as a potential therapeutic target to mitigate liver injury in cholestatic liver diseases. © 2021 The Author(s)
Notes
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