miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease

Pablo Fernández-Tussy, David Fernández-Ramos, Fernando Lopitz-Otsoa, Jorge Simón, Lucía Barbier-Torres, Beatriz Gomez-Santos, Maitane Nuñez-Garcia, Mikel Azkargorta, Virginia Gutiérrez-de Juan, Marina Serrano-Macia, Rubén Rodríguez-Agudo, Paula Iruzubieta, Juan Anguita, Rui E. Castro, Devin Champagne, Mercedes Rincón, Felix Elortza, Anita Arslanow, Marcin Krawczyk, Frank Lammert, Mélanie Kirchmeyer, Iris Behrmann, Javier Crespo, Shelly C. Lu, José M. Mato, Marta Varela-Rey, Patricia Aspichueta, Teresa C. Delgado, María L. Martínez-Chantar

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Glycine N-methyltransferase (GNMT) is the most important and abundant S-adenosylmethionine-dependent methyltransferase in the liver. Fernández-Tussy, Fernández-Ramos, and colleagues describe a new essential role of GNMT in the mitochondria and demonstrate that the recovery of hepatic GNMT levels by targeting the microRNA miR-873-5p emerges as a new therapeutic approach for NAFLD.

Objective: Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression.

Methods: miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy.

Results: We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid β-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment.

Conclusion: GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment.