bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2019‒01‒20
nine papers selected by
Gavin McStay
Staffordshire University

  1. Case Rep Neurol Med. 2018 ;2018 8406712
    Simoncini C, Montano V, Alì G, Costa R, Siciliano G, Mancuso M.
      Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most mutations fall into three mitochondrial tRNAs (tRNAIle, tRNALeu (UUR), and tRNALys) and are responsible for half of the mitochondrial diseasees associated with tRNA mutation, with MERRF, MELAS, mitochondrial myopathy, and Leigh syndrome being the most frequent phenotypes. More than 100 tRNA pathogenetic mutations are described, showing little correlation between the observed clinical phenotype and a specific mitochondrial tRNA mutation. Furthermore different mutation can manifest with similar clinical phenotypes, making the genotype-phenotype correlation difficult. Here we report the case of an Italian 53-year-old woman presenting with a proximal myopathy and the m.5835G>A mutation in MT-TY gene coding for the mitochondrial tRNA Tyrosine gene.
  2. Int J Cardiol. 2019 Jan 05. pii: S0167-5273(18)34315-8. [Epub ahead of print]
    Imai-Okazaki A, Kishita Y, Kohda M, Mizuno Y, Fushimi T, Matsunaga A, Yatsuka Y, Hirata T, Harashima H, Takeda A, Nakaya A, Sakata Y, Kogaki S, Ohtake A, Murayama K, Okazaki Y.
      BACKGROUND: Cardiomyopathy is a reported indicator of poor prognosis in children with mitochondrial disease. However, the association between prognosis and the genetic background of cardiomyopathy in children with mitochondrial disease has yet to be fully elucidated.METHODS AND RESULTS: Of 137 children with mitochondrial disease whose genetic diagnosis was made between 2004 and 2018, 29 had mitochondrial cardiomyopathy (21%). After a median follow-up of 35 months, the overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001). Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively. Among the 21 cardiomyopathy patients who died, two died within one month of birth (COQ4 in one patient, and COX10 in one patient), ten died within one year (BOLA3 in three patients, QRSL1 in two patients, large chromosomal deletions in two patients, MT-ATP6/8 in one patient, MT-TL1 in one patient, and TAZ gene in one patient), and nine died after one year (MT-ND5 in three patients, MT-TL1 in three patients, ACAD9 in one patient, KARS in one patient, and MT-TV in one patient). In the three patients with mitochondrial DNA mutations whose cardiac tissues were available, high heteroplasmy rates in the cardiac tissue were observed for m.8528T>C (90%, died at 2 months of age) and m.3243A>G (90 and 80%, died at 12 and 13 years of age, respectively).
    CONCLUSIONS: In children with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. Genetic analysis coupled with detailed phenotyping could be useful for prognosis.
    Keywords:  Exome sequencing; Infantile cardiomyopathy; Mitochondrial cardiomyopathy; Mitochondrial disease; Mitochondrial respiratory chain complex deficiencies
  3. Postepy Biochem. 2018 Dec 29. 64(4): 300-303
    Bartnik E, Tońska K, Rusecka J.
      Mitochondrial diseases are caused by dysfunction of the mitochondrial oxidative phosphorylation system and can be the result of mutations both in mitochondrial DNA and in nuclear DNA. Mitochondrial diseases collectively describe a diverse group of heritable disorders, which may present at any age and have a wide spectrum of clinical manifestations. This leads to highly variable presentations, making the diagnosis of mitochondrial diseases challenging. Recent advances in genetic testing and novel reproductive options hold great promise for improving the clinical identification and treatment of mitochondrial diseases. In this work we discuss what is new in understanding and diagnosis of mitochondrial diseases.
  4. Adv Anat Embryol Cell Biol. 2019 Jan 14.
    Zouros E, Rodakis GC.
      We recount the basic observations about doubly uniparental inheritance (DUI) of mtDNA in bivalvian mollusks with an emphasis on those that were obtained from work in Mytilus and appeared after the review by Zouros (Evol Biol 40:1-31, 2013). Using this information, we present a new model about DUI that is a revised version of previously suggested models. The model can be summarized as follows. A Mytilus female either provides its eggs with the "masculinizing" factor S and the "sperm mitochondria binding" factor Z, or it does not. This property of the female is determined by two nuclear genes, S and Z, that are always in the on/on or the off/off phase. In fertilized eggs without factors S and Z the embryo develops into a female and the sperm mitochondria are randomly dispersed among cells following development. In fertilized eggs with factors S and Z, the first factor causes the cell to become eventually sperm and the second causes the sperm mitochondria to aggregate and anchor to the nuclear membrane by binding to a specific motif of the sperm-derived mtDNA. Factors S and Z are continuously co-synthesized and co-localized in the cell line from the egg to the sperm. The sperm mitochondria of the aggregate escape the mechanism that eliminates the cell's mitochondria before the formation of the sperm. The rescued mitochondria are subsequently packed into five mega-mitochondria in the sperm and are delivered in the egg.
    Keywords:  Blue mussel; Doubly uniparental inheritance; Mitochondrial DNA inheritance; Mytilus
  5. Dis Model Mech. 2019 Jan 18. pii: dmm.036558. [Epub ahead of print]
    Delerue T, Tribouillard-Tanvier D, Daloyau M, Khosrobakhsh F, Emorine LJ, Friocourt G, Belenguer P, Blondel M, Arnauné-Pelloquin L.
      Mitochondria continually move, fuse and divide and these dynamics are essential for the proper function of these organelles. Indeed, the dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs as well as preserving their integrity. As a consequence, mitochondrial fusion and fission dynamics and the proteins that control these processes, which are conserved from yeast to human, are essential and their disturbances are associated with severe human disorders, including neurodegenerative diseases. For example, mutations in OPA1, that encodes a conserved factor essential for mitochondrial fusion, lead to Optic Atrophy 1, a neurodegeneration that affects the optic nerve eventually leading to blindness. Here, by screening a collection of ∼1,600 repurposed drugs on a fission yeast model, we identified five compounds able to efficiently prevent the lethality associated to the loss of Msp1p, the fission yeast orthologue of OPA1. One compound, hexestrol, was able to rescue both the mitochondrial fragmentation and mtDNA depletion induced by the loss of Msp1p, whereas the second, clomifene, only suppressed the mtDNA defect. Since yeast was already successfully used to identify candidate drugs to treat inherited mitochondrial diseases, this work may provide useful leads for the treatment of optic atrophies such as Optic Atrophy 1 or Leber Hereditary Optic Neuropathy.
    Keywords:  Clomifene; Hexestrol; Mitochondrial DNA; Mitochondrial fusion; OPA1; Yeast
  6. Bioinformatics. 2019 Jan 14.
    Van Strien J, Guerrero-Castillo S, Chatzispyrou IA, Houtkooper RH, Brandt U, Huynen MA.
      Motivation: Complexome profiling combines native gel electrophoresis with mass spectrometry to obtain the inventory, composition and abundance of multiprotein assemblies in an organelle. Applying complexome profiling to determine the effect of a mutation on protein complexes requires separating technical and biological variations from the variations caused by that mutation.Results: We have developed the COmplexome Profiling ALignment (COPAL) tool that aligns multiple complexome profiles with each other. It includes the abundance profiles of all proteins on two gels, using a multidimensional implementation of the dynamic time warping algorithm to align the gels. Subsequent progressive alignment allows us to align multiple profiles with each other. We tested COPAL on complexome profiles from control mitochondria and from Barth syndrome (BTHS) mitochondria, which have a mutation in tafazzin gene that is involved in remodelling the inner mitochondrial membrane phospholipid cardiolipin. By comparing the variation between BTHS mitochondria and controls with the variation among either, we assessed the effects of BTHS on the abundance profiles of individual proteins. Combining those profiles with gene set enrichment analysis allows detecting significantly affected protein complexes. Most of the significantly affected protein complexes are located in the inner mitochondrial membrane (MICOS, prohibitins), or are attached to it (the large ribosomal subunit).
    Availability: COPAL is written in python and is available from gttp://
    Supplementary information: Supplementary data are available at Bioinformatics online.
  7. Mol Genet Metab. 2019 Jan 05. pii: S1096-7192(18)30690-5. [Epub ahead of print]
    Baide-Mairena H, Gaudó P, Marti-Sánchez L, Emperador S, Sánchez-Montanez A, Alonso-Luengo O, Correa M, Grau AM, Ortigoza-Escobar JD, Artuch R, Vázquez E, Del Toro M, Garrido-Pérez N, Ruiz-Pesini E, Montoya J, Bayona-Bafaluy MP, Pérez-Dueñas B.
      AIM: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.METHOD: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.
    RESULTS: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival.
    INTERPRETATION: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.
    Keywords:  Bilateral striatal necrosis; Complex I deficiency; Dystonia; Leigh syndrome; Mitochondrial disease; NDUFAF6
  8. Postepy Biochem. 2018 Dec 29. 64(4): 304-317
    Kucharczyk R, Baranowska E, Rytka J.
      ATP synthase is the last enzyme of the OXPHOS system synthesizing ATP. Mutations in either mitochondrial or nuclear genes encoding subunits of this enzyme (17 polypeptides) cause neurodegenerative diseases. The ATP synthase subunits 8 (ATP8, alias A6L) and a (ATP6) are encoded by the MT-ATP8 and MT-ATP6 mitochondrial genes, respectively. 17 diseases associated mutations were identified in five nuclear genes coding for subunits of this enzyme. 58 mutations were described in the MT-ATP6 and MT-ATP8 genes, among them 36 were deposited in MITOMAP database. For most of them neither their pathogenic character nor the mechanisms are known. This review summarizes what is known about the molecular basis of the ATP synthase deficiencies. We review the mutations in the ATP synthase genes as well as biochemical data obtained from studies of patient's cells and cybrid or yeast models. We include yeast research about drugs selection and their mechanism of action. Moreover we position the mutations into a recently published structural model of the Fo complex and discuss their structural/functional consequences.
  9. Int J Reprod Biomed (Yazd). 2018 Sep;16(9): 571-576
    Mirabutalebi SH, Karami N, Ashrafzadeh HR, Akhvansales Z, Tavakoli M, Ghasemi N.
      Background: The quality of oocyte is often considered as a limiting factor for fertility, especially IVF. Some mitochondrial mutations, particularly the 4977-bp deletion increase with the age. Thus, this mutation can serve as a marker for cell aging, which indicates the reduced quality of the oocytes for fertilization. It has been suggested that this can also be investigated in the blood cells of women with IVF failure.Objective: 1-Determination of the frequency of 4977-bp deletion in women with IVF failure, 2-Investigation of the relationship between 4977-bp deletion and the age of patients.
    Materials and Methods: Polymerase chain reaction was used to detect the 4977-bp deletion in blood samples of 52 IVF failure women and 52 women who had at least one healthy child. After polymerase chain reaction with deleted and wild-type primers, the products were examined using agarose gel electrophoresis.
    Results: 48.07% of women with IVF failure and 34.62% of healthy women had a mitochondrial 4977-bp deletion, with p=0.163 and OR: 1.749. Also, in association with the age of these patients and the frequency of 4977-bp mutation, p and OR were obtained 0.163 and 1.749, respectively and frequency of this mutation was higher in patients over 35 yr old compared to other subgroups (Patients ≥35: 57.69).
    Conclusion: According to the findings of this study, there is no a significant relationship between the frequency of mitochondrial 4977-bp mutation and failure in IVF.
    Keywords:  Cell aging; In vitro fertilization; Mitochondria; Mutation