bims-cytox1 2018-02-04 papers

Mitochondrion. 2018 Jan 27. pii: S1567-7249(17)30154-X. [Epub ahead of print]

Phosphorylation of the outer membrane mitochondrial protein OM64 influences protein import into mitochondria.

Catharina Nickel, Regina Horneff, Ralf Heermann, Boris Neumann, Kirsten Jung, Jürgen Soll, Serena Schwenkert.

Mitochondrial localized proteins are mostly synthesized in the cytosol and translocated across the outer mitochondrial membrane via the translocase of the outer membrane (TOM) complex. Although the channel protein is conserved among eukaryotes, the receptor proteins are more divergent and show features specific to the plant lineage. OM64, which is a paralogue of the chloroplast docking protein Toc64, is unique to plants. However, due to the presence of a cytosolic exposed TPR domain it might functionally replace yeast/mammalian Tom70, which is not found in plant mitochondria, by interacting with the C-terminal (M)EEVD motif of the heat shock proteins Hsp90 and Hsp70. In this study, we show that OM64 is phosphorylated within its TPR domain. Using isothermal titration calorimetry it could be demonstrated that phosphorylation reduces the binding affinity of OM64 to Hsp90. Moreover, in vivo expression of genes encoding different OM64 variants in planta revealed that phosphorylation of OM64 impairs the import efficiency of the mitochondrial preprotein pFAD, a subunits of the mitochondrial ATP synthase. In summary, our data provide significant insight into the fine-tuning mechanisms of mitochondrial protein import mediated by phosphorylation of the cytosolic exposed receptor protein OM64.

Keywords: Arabidopsis thaliana; Hsp90; Mitochondria; Protein import; TPR domain

DOI: https://doi.org/10.1016/j.mito.2018.01.005

Exp Ther Med. 2018 Jan;15(1): 13-18

Recent perspectives of pediatric mitochondrial diseases.

Junhua Cao, Hongwei Wu, Zhenguang Li.

Mitochondrial disorders are amongst the most common groups of inborn errors of metabolism. They are caused by deficiencies in the final pathway of the cellular energy production, the mitochondrial respiratory chain. The disorders are clinically and genetically heterogeneous and the aetiology could be found in the mitochondrial, or in the nuclear genome. We searched important e-databases for the collection of latest literature on the mitochondrial disease especially in pediatric population. Most of the studies in the recent past have focused on the understanding of the clinical phenotypes and pathophysiological mechanisms. Leigh syndrome is a common severe, neurodegenerative disease of early childhood. A defect in the POLG gene is another common observation in most of the cases leading to Alpers syndrome. The review concludes that pediatric mitochondrial disorders are severe, progressive and usually multi-systemic. Further, whole genome sequencing is an excellent diagnostic option.

Keywords: mitochondrial disorders; pediatrics

DOI: https://doi.org/10.3892/etm.2017.5385

Graefes Arch Clin Exp Ophthalmol. 2018 Jan 29.

Mitochondrial A3243G mutation results in corneal endothelial polymegathism.

Mathieu F Bakhoum, Wei-Pu Wu, Eugenia C White, Jesse D Sengillo, Christian Sanfilippo, Marcelle M Morcos, K Bailey Freund, Henry D Perry, David Sarraf, Stephen H Tsang.

PURPOSE: The mitochondrial DNA point mutation A3243G leads to a spectrum of syndromes ranging from MIDD to MELAS. Ocular manifestations include pattern macular dystrophy and concentric perifoveal atrophy. Given the high metabolic demand of corneal endothelial cells, we performed specular biomicroscopy analysis in patients harboring the mitochondrial DNA point mutation A3243G to assess for the associated presence of corneal endothelial abnormalities.
METHODS: We present a case series with participants from two institutions. Patients diagnosed with macular dystrophy associated with MIDD or MELAS, and the mitochondrial DNA point mutation A3243G were recruited. Exclusion criteria included a prior diagnosis, or a positive family history, of endothelial corneal dystrophy. Slit-lamp corneal examination and specular biomicroscopy were performed. Corneal endothelial cell count, cell size and polymegathism, and central corneal thickness were assessed. Patients diagnosed with MIDD or MELAS based on clinical history and examination were genetically tested for the mitochondrial DNA point mutation A3243G using pyrosequencing.
RESULTS: Five patients (two male and three female participants) from five different families, and with different ethnic backgrounds, met the inclusion criteria. Their ages ranged from 41 to 60 years. Corneal endothelial changes observed using slit-lamp examination were primarily mild to rare guttata. Specular biomicroscopy displayed mainly polymegathism associated with guttata. The average endothelial cell count was 2358 ± 456 cells per mm2, the average endothelial cell size was 442 ± 103 μm2 and the average central corneal thickness (CCT) was 551 ± 33 μm. These values were similar to that of the average population. The average coefficient of variation (COV), an index of heterogeneity in cell size, was 42.0 ± 4.1%. When compared to the average population, the average COV was significantly higher than predicted for the patients' age. None of the patients had signs of corneal edema. One patient had a pre-Descemet's opacity.
CONCLUSIONS: In patients with the mitochondrial DNA point mutation A3243G, corneal endothelial polymegathism is present. This is mainly associated with mild guttata. The findings of corneal endothelial cell polymegathism may be a biomarker of mitochondrial disease, specifically in patients with the mitochondrial DNA A3243G mutation.

Keywords: Endothelial corneal dystrophy; Genetics; Mitochondrial diseases; Retinal dystrophy; Specular microscopy

DOI: https://doi.org/10.1007/s00417-018-3914-z