bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2019‒02‒03
four papers selected by
Gavin McStay
Staffordshire University


  1. Free Radic Res. 2018 Dec;52(11-12): 1250-1255
    Li G, Qin Y.
      Mitochondrial translation system executes the biosynthesis of mitochondrial DNA encoded polypeptides that are the core subunits of oxidative phosphorylation complexes. Recently, we reported that elongation factor 4 (EF4) is a key quality control factor in bacterial and mitochondrial translation regulating tRNA translocation and modulating cellular responses via a direct cross-talk with cytoplasmic translation machinery. Here, we made a brief review on mtEF4-regulated mitochondrial translation, respiratory chain biogenesis and the production of reactive oxygen species (ROS). We will discuss the influence of mtEF4 on the electron transport chain, especially at respiratory chain complex IV, which could result in cytochrome c peroxidase formation, electron leakage from electron transport chain and ROS increase.
    Keywords:  EF4; ROS; mitochondrial translation; ribosome
    DOI:  https://doi.org/10.1080/10715762.2018.1479063
  2. Mol Genet Genomic Med. 2019 Jan 31. e00582
    Tang Y, Qin Q, Xing Y, Guo D, Di L, Jia J.
      BACKGROUND: Mutations in the mitochondrial alanyl-transfer (t)RNA synthetase 2 (AARS2,OMIM:612035) have been linked to leukoencephalopathy recently. Till now, there have been 19 cases reported so far. However, the clinical and genetic characteristics of this disease are not fully understood. We reported an adult-onset male leukoencephalopathy patient related to novel AARS2 gene mutations and reviewed all previous cases regarding the clinical and genetic features of AARS2 leukoencephalopathy.METHODS: The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with AARS2 gene mutations.
    RESULTS: Here, we present a 30-year-old man with progressive motor deficits in the right lower limb and severe cerebellar ataxia for one year. MRI revealed extensive white matter lesions in periventricular regions and along the corticospinal tract. Genetic analysis revealed two new heterogeneous missense mutations in AARS2: c.179C>A and c.1703_1704del. We described the ragged red fiber (RRF) for the first time, suggesting that AARS2-related leukoencephalopathy be a new variant of mitochondrial encephalomyopathy. Gradual improvement in motor function was observed with intravenous coenzyme complex treatment. We also summarized our case and all previously reported cases to provide an overview of AARS2-related late-onset leukoencephalopathy. Then, we compared clinical and neuroimaging features of AARS2-related leukoencephalopathy with three other frequently diagnosed types of adult-onset leukoencephalopathy to provide insight into diagnostic strategies.
    CONCLUSION: The characteristic MRI abnormalities and clinical symptoms described here may help to distinguish AARS2-related leukoencephalopathy from other adult-onset leukoencephalopathies. The combination of encephalopathy and myopathy strongly suggest that AARS2-related leukoencephalopathy is a new variant of mitochondrial encephalomyopathy. The response to coenzyme complex will shed light on future therapy investigation.
    Keywords:  AARS2 leukoencephalopathy; alanyl-transfer (t)RNA synthetase 2; leukoencephalopathies; mitochondrial encephalomyopathy
    DOI:  https://doi.org/10.1002/mgg3.582
  3. Mol Genet Metab. 2019 Jan 25. pii: S1096-7192(18)30770-4. [Epub ahead of print]
    Uittenbogaard M, Wang H, Zhang VW, Wong LJ, Brantner CA, Gropman A, Chiaramello A.
      In this study, we report the metabolic consequences of the m.1630 A > G variant in fibroblasts from the symptomatic proband affected with the mitochondrial encephalomyopathy lactic acidosis and stroke-like episode Syndrome and her asymptomatic mother. By long-range PCR followed by massively parallel sequencing of the mitochondrial genome, we accurately measured heteroplasmy in fibroblasts from the proband (89.6%) and her mother (94.8%). Using complementary experimental approaches, we show a functional correlation between manifestation of clinical symptoms and bioenergetic potential. Our mitochondrial morphometric analysis reveals a link between defects of mitochondrial cristae ultrastructure and symptomatic status. Despite near-homoplasmic level of the m.1630A > G variant, the mother's fibroblasts have a normal OXPHOS metabolism, which stands in contrast to the severely impaired OXPHOS response of the proband's fibroblasts. The proband's fibroblasts also exhibit glycolysis at near constitutive levels resulting in a stunted compensatory glycolytic response to offset the severe OXPHOS defect. Whole exome sequencing reveals the presence of a heterozygous nonsense VARS2 variant (p.R334X) exclusively in the proband, which removes two thirds of the VARS2 protein containing key domains interacting with the mt-tRNAval and may play a role in modulating the penetrance of the m.1630A > G variant despite similar near homoplasmic levels. Our transmission electron microscopy study also shows unexpected ultrastructural changes of chromatin suggestive of differential epigenomic regulation between the proband and her mother that may explain the differential OXPHOS response between the proband and her mother. Future study will decipher by which molecular mechanisms the nuclear background influences the penetrance of the m.1630 A > G variant causing MELAS.
    Keywords:  Glycolysis; MELAS; Metabolic adaptability; Mitochondrial tRNA(Val); OXPHOS; Whole exome sequencing
    DOI:  https://doi.org/10.1016/j.ymgme.2019.01.022
  4. eNeurologicalSci. 2019 Mar;14 74-76
    Miyaue N, Yamanishi Y, Tada S, Ando R, Yabe H, Nagai M, Nomoto M.
      •LHON cases can show brainstem lesions without visual impairment.•There can be inconsistency between MRI finding and clinical symptom in LHON cases.•Auditory pathways may be often involved in LHON cases.
    Keywords:  Brainstem lesions; Leber hereditary optic neuropathy; Leigh syndrome; Mitochondrial disorder
    DOI:  https://doi.org/10.1016/j.ensci.2019.01.002