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

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 (Gfm1(R671C)(/)(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 Gfm1(R671C)(/)(R671C) mice showed partial reductions of in organello mitochondrial translation and respiratory complex IV enzyme activity in the liver. Compound heterozygous Gfm1(R671C)(/-) showed a more pronounced decrease of EFG1 protein in liver and brain mitochondria, as compared with Gfm1(R671C)(/)(R671C) mice. At 8 weeks of age, their mitochondrial translation rates were significantly reduced in both tissues. Additionally, Gfm1(R671C)(/-) 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 Gfm1(R671C)(/-) 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.

Automated summary

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a mitochondrial translation disorder caused by mutations in GFM1. Mouse models with Gfm1 knock-in and knock-out mutations were generated to study COXPD1. The knock-in mice showed normal growth but had decreased mitochondrial EFG1 protein content, while the knock-out mice were embryonically lethal. The compound heterozygous mice had impaired mitochondrial translation and respiratory chain dysfunction, making them suitable for studying COXPD1.