bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2019‒02‒24
seven papers selected by
Gavin McStay
Staffordshire University


  1. J Neurol Sci. 2019 Feb 06. pii: S0022-510X(19)30071-1. [Epub ahead of print]399 69-75
    Tolomeo D, Rubegni A, Severino M, Pochiero F, Bruno C, Cassandrini D, Madeo A, Doccini S, Pedemonte M, Rossi A, D'Amore F, Donati MA, Di Rocco M, Santorelli FM, Nesti C.
      Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.
    Keywords:  Complex I deficiency; Leigh syndrome; ND3 gene; mtDNA
    DOI:  https://doi.org/10.1016/j.jns.2019.02.010
  2. Mol Cell. 2019 Feb 01. pii: S1097-2765(19)30013-9. [Epub ahead of print]
    Zhang Y, Wang ZH, Liu Y, Chen Y, Sun N, Gucek M, Zhang F, Xu H.
      We have previously proposed that selective inheritance, the limited transmission of damaging mtDNA mutations from mother to offspring, is based on replication competition in Drosophila melanogaster. This model, which stems from our observation that wild-type mitochondria propagate much more vigorously in the fly ovary than mitochondria carrying fitness-impairing mutations, implies that germ cells recognize the fitness of individual mitochondria and selectively boost the propagation of healthy ones. Here, we demonstrate that the protein kinase PINK1 preferentially accumulates on mitochondria enriched for a deleterious mtDNA mutation. PINK1 phosphorylates Larp to inhibit protein synthesis on the mitochondrial outer membrane. Impaired local translation on defective mitochondria in turn limits the replication of their mtDNA and hence the transmission of deleterious mutations to the offspring. Our work confirms that selective inheritance occurs at the organelle level during Drosophila oogenesis and provides molecular entry points to test this model in other systems.
    Keywords:  AKAP1; DNA replication; Larp1; PINK1; local protein synthesis; mitochondria; mitochondrial quality control; mtDNA; oogenesis; selective inheritance
    DOI:  https://doi.org/10.1016/j.molcel.2019.01.013
  3. Elife. 2019 Feb 18. pii: e41927. [Epub ahead of print]8
    Ali AT, Boehme L, Carbajosa G, Seitan VC, Small KS, Hodgkinson A.
      Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (TBRG4, MTPAP and LONP1), implicating genetic mechanisms that act in trans across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.
    Keywords:  chromosomes; gene expression; genetics; genomics; human
    DOI:  https://doi.org/10.7554/eLife.41927
  4. Mol Biol Evol. 2019 Feb 20. pii: msz036. [Epub ahead of print]
    Yan Z, Ye G, Werren JH.
      The mitochondrion is a pivotal organelle for energy production, and includes components encoded by both the mitochondrial and nuclear genomes. Functional and evolutionary interactions are expected between the nuclear and mitochondrial encoded components. The topic is of broad interest in biology, with implications to genetics, evolution, and medicine. Here we compare the evolutionary rates of mitochondrial proteins and ribosomal RNAs to rates of mitochondria-associated nuclear-encoded proteins, across the major orders of holometabolous insects. There are significant evolutionary rate correlations (ERCs) between mitochondrial-encoded and mitochondria-associated nuclear-encoded proteins, which is likely driven by different rates of mitochondrial sequence evolution and correlated changes in the interacting nuclear-encoded proteins. The pattern holds after correction for phylogenetic relationships and considering protein conservation levels. Correlations are stronger for both nuclear-encoded OXPHOS proteins that are in contact with mitochondrial OXPHOS proteins and for nuclear-encoded mitochondrial ribosomal amino acids directly contacting the mitochondrial rRNAs. We find that ERC between mitochondrial- and nuclear-encoded proteins is a strong predictor of nuclear-encoded proteins known to interact with mitochondria, and ERC shows promise for identifying new candidate proteins with mitochondrial function. Twenty-three additional candidate nuclear-encoded proteins warrant further study for mitochondrial function based on this approach, including proteins in the minichromosome maintenance helicase (MCM) complex.
    Keywords:  coevolution; compensatory evolution; insect; mitochondrion; substitution rates
    DOI:  https://doi.org/10.1093/molbev/msz036
  5. Pol J Pathol. 2018 ;pii: 34483. [Epub ahead of print]69(4): 422-431
    Felczak P, Stępniak I, Kowalski P, Stępień T, Wierzba-Bobrowicz T.
      Our studies concerned skeletal muscle biopsy specimens from a patient with clinically suspected MERRF syndrome, confirmed by genetic tests showing the presence of point mutation in the m.8344A> G in the tRNALys gene. Ultrastructurally, extensive damage of mitochondria in skeletal muscle fibres was observed, including the presence of two types of mitochondrial inclusions. Mild damage of mitochondria was revealed in small blood vessels and the presence of calcium deposits in the vascular walls were observed. The differences in mitochondrial damage may be related to different origin and expenditure of biologically useful energy in these cells.
    Keywords:   A8344G mutation; abnormal mitochondria; calcium precipitate; ultrastructure; MERRF
    DOI:  https://doi.org/10.5114/pjp.2018.80904
  6. J Cell Physiol. 2019 Feb 18.
    Salazar C, Elorza AA, Cofre G, Ruiz-Hincapie P, Shirihai O, Ruiz LM.
      HIG2A promotes cell survival under hypoxia and mediates the assembly of complex III and complex IV into respiratory chain supercomplexes. In the present study, we show that human HIGD2A and mouse Higd2a gene expressions are regulated by hypoxia, glucose, and the cell cycle-related transcription factor E2F1. The latter was found to bind the promoter region of HIGD2A. Differential expression of the HIGD2A gene was found in C57BL/6 mice in relation to tissue and age. Besides, the silencing of HIGD2A evidenced the modulation of mitochondrial dynamics proteins namely, OPA1 as a fusion protein increases, while FIS1, a fission protein, decreases. Besides, the mitochondrial membrane potential (ΔΨm) increased. The protein HIG2A is localized in the mitochondria and nucleus. Moreover, we observed that the HIG2A protein interacts with OPA1. Changes in oxygen concentration, glucose availability, and cell cycle regulate HIGD2A expression. Alterations in HIGD2A expression are associated with changes in mitochondrial physiology.
    Keywords:  E2F1; HIG2A; OPA1; OXPHOS supercomplexes; cell cycle; hypoxia; mitochondrial dynamics
    DOI:  https://doi.org/10.1002/jcp.28362
  7. BMJ Open. 2019 Feb 19. 9(2): e027004
    de Marco G, Garcia-Garcia AB, Real JT, Gonzalez-Albert V, Briongos-Figuero LS, Cobos-Siles M, Lago-Sampedro A, Corbaton A, Teresa Martinez-Larrad M, Carmena R, Martin-Escudero JC, Rojo-Martínez G, Chaves FJ.
      OBJECTIVE: To study the association of genes involved in the mitochondrial respiratory chain (MRC) pathway with body mass index (BMI) and obesity risk.DESIGN: This work studies three cross-sectional populations from Spain, representing three provinces: HORTEGA (Valladolid, Northwest/Centre), SEGOVIA (Segovia, Northwest/centre) and PIZARRA (Malaga,South).
    SETTING: Forty-eight single nucleotide polymorphisms (SNPs) from MRC genes were selected and genotyped by SNPlex method. Association studies with BMI and obesity risk were performed for each population. These associations were then verified by analysis of the studied population as a whole (3731 samples).
    PARTICIPANTS: A total of 3731 Caucasian individuals: 1502 samples from HORTEGA, 988 from PIZARRA and 1241 from SEGOVIA.
    RESULTS: rs4600063 (SDHC), rs11205591 (NDUFS5) and rs10891319 (SDHD) SNPs were associated with BMI and obesity risk (p values for BMI were 0.04, 0.0011 and 0.0004, respectively, and for obesity risk, 0.0072, 0.039 and 0.0038). However, associations between rs4600063 and BMI and between these three SNPs and obesity risk are not significant if Bonferroni correction is considered. In addition, rs11205591 and rs10891319 polymorphisms showed an additive interaction with BMI and obesity risk.
    CONCLUSIONS: Several polymorphisms from genes coding MRC proteins may be involved in BMI variability and could be related to the risk to become obese in the Spanish general population.
    Keywords:  mitochondrial respiratory chain; obesity; snp
    DOI:  https://doi.org/10.1136/bmjopen-2018-027004