Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations.

Abstract

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1-/- ) were embryonically lethal, whereas homozygous KI (Gfm1R671C/R671C ) mice were viable and showed normal growth. R671C mutation in Gfm1 caused drastic reductions in the mitochondrial EFG1 protein content in different organs. Six- to eight-week-old Gfm1R671C/R671C mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1R671C/- showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1R671C/R671C mice. At 8 weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1R671C/- mice showed combined oxidative phosphorylation deficiency (reduced complex I and IV enzyme activities in liver and brain), and blue native polyacrylamide gel electrophoresis analysis revealed lower amounts of both affected complexes. We conclude that the compound heterozygous Gfm1R671C/- mouse presents a clear dysfunctional molecular phenotype, showing impaired mitochondrial translation and combined respiratory chain dysfunction, making it a suitable animal model for the study of COXPD1.

• Authors: Miguel Molina-Berenguer, Ferran Vila-Julià, Sandra Pérez-Ramos, Maria Teresa Salcedo-Allende, Yolanda Cámara, Javier Torres-Torronteras, Ramon Martí
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 36 Issue 1 Pg. e22091 (01 2022) ISSN: 1530-6860 [Electronic] United States
• PMID: 34919756 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Federation of American Societies for Experimental Biology.

Chemical References

• Mitochondrial Proteins
• Peptide Elongation Factor G
• Electron Transport Complex IV

Topics

• Amino Acid Substitution
• Animals
• Disease Models, Animal
• Electron Transport Complex IV (genetics, metabolism)
• Hepatic Encephalopathy (genetics, metabolism)
• Metabolism, Inborn Errors (genetics, metabolism)
• Mice
• Mice, Knockout
• Mitochondria, Liver (genetics, metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Mutation, Missense
• Oxidative Phosphorylation
• Peptide Elongation Factor G (genetics, metabolism)
• Protein Biosynthesis