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Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness among young adults. In this study, we investigated the potential of four quinone analogues (CoQ1, CoQ10, decylubiquinone and idebenone) in compensating for the deleterious effect of the m.11778G>A mitochondrial DNA mutation. The LHON fibroblast cell lines tested exhibited reduced cell growth, impaired mitochondrial bioenergetics and elevated levels of reactive oxygen species (ROS). Idebenone increased ATP production and reduced ROS levels, but the effect was partial and cell-specific. The remaining quinone analogues had variable effects and a negative impact on certain mitochondrial parameters was observed in some cell lines., Highlights • Idebenone can partially compensate for the deleterious effect of the m.11778G > A mitochondrial DNA mutation. • The beneficial effect of idebenone on mitochondrial function was only observed in a subgroup of patient-derived fibroblasts. • Quinone analogues can have a detrimental effect on certain mitochondrial parameters when tested in vitro.

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases. We report two novel GFM1 mutations in two unrelated patients with encephalopathy and liver failure respectively. The first patient had intrauterine growth retardation, seizures, encephalopathy and developmental delay. Brain MRI showed hypoplasia of the vermis and severe pontine atrophy of the brainstem that were similar to those reported in patients with mitochondrial translation deficiencies. The second patient had liver failure with hypoglycemia. Respiratory chain analysis showed a complex IV deficiency in muscle of both patients. A 10K SNP genotyping detected several regions of homozygosity in the two patients. In vitro translation deficiency prompted us to study genes involved in mitochondrial translation. Therefore, we sequenced the GFM1 gene, encoding the mitochondrial translation factor EFG1, included in a shared homozygous region and identified two different homozygous mutations (R671C and L398P). Modeling studies of EFG1 protein suggested that the R671C mutation disrupts an inter-subunit interface and could locally destabilize the mutant protein. The second mutation (L398P) disrupted the H-bond network in a rich-beta-sheet domain, and may have a dramatic effect on local structure. GFM1 mutations have been seldom reported and are associated with different clinical presentation. By modeling the structure of the protein and the position of the various mutations we suggest that the clinical phenotypes of the patients could be related to the localization of the mutations.

The infantile presentation of mitochondrial respiratory chain defects frequently simulates acute bacterial infection and sepsis. Consequently, broad spectrum antibiotic therapy is often initiated before definitive diagnosis is reached and without taking into consideration the potential harm of antibiotics affecting mitochondrial translation. Here, we demonstrate that some commonly used translation-targeted antibiotics adversely affect the growth of fibroblasts from patients with defective mitochondrial translation systems. In addition, we show that these antibiotics inhibit mitochondrial translation in vitro. Our results suggest that patients with mitochondrial translation defects may be more vulnerable to toxic-side-effects following the administration of certain translation-targeted antibiotics.