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.

Elevated temperatures reduce population‐specific transcriptional plasticity in developing lake sturgeon (Acipenser fulvescens)

“…Transcriptional markers of dysfunction and resulting damages were apparent at 20°C in northern Burntwood River sturgeon and were more extreme when compared to southern Winnipeg River sturgeon, highlighting potential population‐specific mitochondrial capacity. Additionally, a highly differentially expressed hub transcript ( gfm1 ) key to mitochondrial translation and oxidative phosphorylation (Berenguer et al, 2021) was altered as temperatures increased. Aside from the direct effects of decreased ATP production and increased reactive oxygen species damage, a decline in mitochondrial function also has implications for stress signalling, viral immune response and formation of heme as well as iron cluster assemblies required for oxygen transport and numerous cellular processes (Aijoka et al, 2006; Braymer et al, 2021; Hernansanz‐Agustin et al, 2020; Karnkokowska et al, 2016; Lin et al, 2006; Qin et al, 2010; Tovar et al, 2003).…”

Severe Acute Liver Dysfunction Induces Delayed Hepatocyte Swelling and Cytoplasmic Vacuolization, and Delayed Cortical Neuronal Cell Death

“…A large amount of glutamic acid is taken up by neurons, disturbing the neurotransmitter balance, and thus inducing neuronal dysfunction. It has been suggested that mitochondrial dysfunction in neurons, caused by altered neurotransmission alone, may lead to neuronal atrophy [ 40 , 41 ].…”

Illuminating mitochondrial translation through mouse models

“…Interestingly, a patient with a mutation in the corresponding domain of TSFM, presented with infantile encephalocardiomyopathy and sensorineural hearing loss [ 130 ], thereby indicating that even disruption to the same interaction site can lead to distinct disease presentations, consistent with the heterogeneity typically observed in mitochondrial diseases. To explore these complex human disease presentations, a pathogenic variant, R671C, was introduced into the Gfm1 gene in mice, and found to cause a significantly milder disease than that observed in patients [ 131 ]. The reason for this was unclear, because residue R671 in both the human and mouse GFM1 protein is essential for its stability and weakens its interaction with the ribosome.…”

“…The reason for this was unclear, because residue R671 in both the human and mouse GFM1 protein is essential for its stability and weakens its interaction with the ribosome. While patients developed hepatoencephalopathy, the mutant mice displayed only a mild molecular phenotype in the liver, including significant decrease in Complex IV activity and a decreased translation rate [ 131 ]. In patients with fatal hepatopathy due to a GFM1 mutation, OXPHOS dysfunction appeared to correlate with residual protein abundance, which was absent in the liver, but maintained at 60% of control in heart, therefore maintaining sufficient translation capacity in this tissue [ 132 ].…”