Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

• Published in: Cell Vol. 177; no. 4; pp. 881 - 895.e17
• Main Authors: Hernández-Alvarez, María Isabel, Sebastián, David, Vives, Sara, Ivanova, Saška, Bartoccioni, Paola, Kakimoto, Pamela, Plana, Natalia, Veiga, Sónia R., Hernández, Vanessa, Vasconcelos, Nuno, Peddinti, Gopal, Adrover, Anna, Jové, Mariona, Pamplona, Reinald, Gordaliza-Alaguero, Isabel, Calvo, Enrique, Cabré, Noemí, Castro, Rui, Kuzmanic, Antonija, Boutant, Marie, Sala, David, Hyotylainen, Tuulia, Orešič, Matej, Fort, Joana, Errasti-Murugarren, Ekaitz, Rodrígues, Cecilia M.P., Orozco, Modesto, Joven, Jorge, Cantó, Carles, Palacin, Manuel, Fernández-Veledo, Sonia, Vendrell, Joan, Zorzano, Antonio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.05.2019
• Subjects: animal models; Animals; biopsy; Disease Models, Animal; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - physiology; fatty liver; fibrosis; GTP Phosphohydrolases - metabolism; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; inflammation; Inflammation - metabolism; liver; Liver - pathology; Liver Diseases - etiology; Liver Diseases - metabolism; liver neoplasms; Male; MAMs; Mfn2; Mice; Mice, Inbred C57BL; mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; NASH; Non-alcoholic Fatty Liver Disease - metabolism; patients; phenotype; phosphatidylethanolamines; phosphatidylserine; phosphatidylserines; Phosphatidylserines - metabolism; phospholipid transfer; Primary Cell Culture; Protein Transport - physiology; Signal Transduction; triacylglycerols; Triglycerides - metabolism; phosphatidylserine; Mfn2; MAMs; NASH; phospholipid transfer; mitochondria
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.04.010

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease. [Display omitted] •Mfn2 binds directly and specifically to phosphatidylserine (PS)•Hepatic Mfn2 deficiency causes a reduced transfer of PS from ER to mitochondria•Mfn2 ablation in liver causes a NASH-like phenotype and liver cancer•A defective transfer of PS from ER to mitochondria causes liver disease The mitochondrial protein mitofusin 2 binds and transfers phosphatidylserine across mitochondria-ER contacts, and perturbation of this process leads to aberrant lipid metabolism and liver diseases like NASH, NAFLD, and cancer.