bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2019‒12‒15
nine papers selected by
Gavin McStay
Staffordshire University

  1. Appl Microbiol Biotechnol. 2019 Dec 12.
    Guo X, Zhang M, Gao Y, Cao G, Lu D, Li W.
      In this study, combined genome, transcriptome, and metabolome analysis was performed for eight Saccharomyces cerevisiae mitochondrial respiration-deficient mutants. Each mutant exhibited a unique nuclear genome mutation pattern; the nuclear genome mutations, and thus potentially affected genes and metabolic pathways, showed a co-occurrence frequency of ≤ 3 among the eight mutants. For example, only a lipid metabolism-related pathway was likely to be affected by the nuclear genome mutations in one of the mutants. However, large deletions in the mitochondrial genome were the shared characteristic among the eight mutants. At the transcriptomic level, lipid metabolism was the most significantly enriched Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway for differentially expressed genes (DEGs) co-occurring in both ≥ 4 and ≥ 5 mutants. Any identified DEG enriched in lipid metabolism showed the same up-/down-regulated pattern among nearly all eight mutants. Further, 126 differentially expressed lipid species (DELS) were identified, which also showed the same up-/down-regulated pattern among nearly all investigated mutants. It was conservatively demonstrated that the similar change pattern of lipid metabolism in the entire investigated mutant population was attributed to mitochondrial dysfunction. The change spectrum of lipid species was presented, suggesting that the number and change degree of up-regulated lipid species were higher than those of down-regulated lipid species. Additionally, energy storage lipids increased in content and plasma-membrane phospholipid compositions varied in the relative proposition. The results for the genome, transcriptome, and lipidome were mutually validated, which provides quantitative data revealing the roles of mitochondria from a global cellular perspective.
    Keywords:  Lipid metabolism; Mitochondria; Multi-omics analysis; Respiration-deficient mutant; Saccharomyces cerevisiae
  2. Free Radic Biol Med. 2019 Dec 05. pii: S0891-5849(19)31565-5. [Epub ahead of print]
    Burger N, Logan A, Prime TA, Mottahedin A, Caldwell ST, Krieg T, Hartley RC, James AM, Murphy MP.
      Coenzyme Q (CoQ) is an essential cofactor, primarily found in the mitochondrial inner membrane where it functions as an electron carrier in the respiratory chain, and a lipophilic antioxidant. The redox state of the CoQ pool is the ratio of its oxidised (ubiquinone) and reduced (ubiquinol) forms, and is a key indicator of mitochondrial bioenergetic and antioxidant status. However, the role of CoQ redox state in vivo is poorly understood, because determining its value is technically challenging due to redox changes during isolation, extraction and analysis. To address these problems, we have developed a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay that enables us to extract and analyse both the CoQ redox state and the magnitude of the CoQ pool with negligible changes to redox state from small amounts of tissue. This will enable the physiological and pathophysiological roles of the CoQ redox state to be investigated in vivo.
    Keywords:  CoQ(10); CoQ(9); Coenzyme Q; Mass spectrometry; Mitochondria; Oxidative stress; Redox state
  3. BMB Rep. 2019 Dec 10. pii: 4830. [Epub ahead of print]
    Park D, Lee S, Min KT.
      The mitochondrial genome encodes 13 proteins that are components of the oxidative phosphorylation system (OXPHOS), suggesting that precise regulation of these genes is crucial for maintaining OXPHOS functions, including ATP production, calcium buffering, cell signaling, ROS production, and apoptosis. Furthermore, heteroplasmy or mis-regulation of gene expression in mitochondria frequently is associated with human mitochondrial diseases. Thus, various approaches have been developed to investigate the roles of genes encoded by the mitochondrial genome. In this review, we will discuss a wide range of techniques available for investigating the mitochondrial genome, mitochondrial transcription, and mitochondrial translation, which provide a useful guide to understanding mitochondrial gene expression.
  4. Mol Genet Genomic Med. 2019 Dec 10. e1085
    Vitale O, Preste R, Palmisano D, Attimonelli M.
      BACKGROUND: Human mitochondrial DNA has an important role in the cellular energy production through oxidative phosphorylation. Therefore, this process may be the cause and have an effect on mitochondrial DNA mutability, functional alteration, and disease onset related to a wide range of different clinical expressions and phenotypes. Although a large part of the observed variations is fixed in a population and hence expected to be benign, the estimation of the degree of the pathogenicity of any possible human mitochondrial DNA variant is clinically pivotal.METHODS: In this scenario, the establishment of standard criteria based on functional studies is required. In this context, a "data and text mining" pipeline is proposed here, developed using the programming language R, capable of extracting information regarding mitochondrial DNA functional studies and related clinical assessments from the literature, thus improving the annotation of human mitochondrial variants reported in the HmtVar database.
    RESULTS: The data mining pipeline has produced a list of 1,073 Pubmed IDs (PMIDs) from which the text mining pipeline has retrieved information on 932 human mitochondrial variants regarding experimental validation and clinical features.
    CONCLUSIONS: The application of the pipeline will contribute to supporting the interpretation of pathogenicity of human mitochondrial variants by facilitating diagnosis to clinicians and researchers faced with this task.
    Keywords:  annotation; mitochondria; pathogenicity; variant
  5. Mitochondrion. 2019 Dec 07. pii: S1567-7249(19)30200-4. [Epub ahead of print]
    Mance LG, Mawla I, Shell SM, Cahoon AB.
      The relatively recent focus on the widespread occurrence and abundance of circular RNAs (circRNA) in the human cell nucleus has sparked an intensive interest in their existence and possible roles in cell gene expression and physiology. The presence of circRNAs in mammalian mitochondria, however, has been under-explored. Mitochondrial mRNAs differ from those produced from nuclear genes because they lack introns and are transcribed as poly-cistronic transcripts that are endonucleolytically cleaved, leaving transcripts with very small 5' and 3' UTRs. Circular RNAs have been identified in the semi-autonomous organelles of single-celled organisms and plants but their purpose has not been clearly demonstrated. The goal of our project was to test the hypothesis, processed mRNAs are circularized in vertebrate mitochondria as a necessary RNA processing step prior to translation. Mitochondrial mRNAs were isolated from the human cell line HEK293 and evidence of circularization sought by treating RNA with RNAse-R and then amplifying putative 3'-5' junction sites. Sequence results demonstrated the occurrence of mRNA circularization within each coding region of the mitochondrial genome. However, in most cases the circRNAs carried coding regions that had been truncated, suggesting they were not translatable. Quantification of the circularized versions of the mRNAs revealed they comprise a small portion (∼10%) of the total mRNA. These findings demonstrate that mRNA circularization occurs in mammalian mitochondria but it does not appear to play a role in making translatable mRNAs.
    Keywords:  Circular RNA; Organelle; mammalian mitochondria; mitochondrial RNA processing
  6. Biol Chem. 2019 Dec 09. pii: /j/bchm.ahead-of-print/hsz-2019-0337/hsz-2019-0337.xml. [Epub ahead of print]
    Aretz I, Jakubke C, Osman C.
      Mitochondria supply virtually all eukaryotic cells with energy through ATP production by oxidative phosphoryplation (OXPHOS). Accordingly, maintenance of mitochondrial function is fundamentally important to sustain cellular health and various diseases have been linked to mitochondrial dysfunction. Biogenesis of OXPHOS complexes crucially depends on mitochondrial DNA (mtDNA) that encodes essential subunits of the respiratory chain and is distributed in multiple copies throughout the mitochondrial network. During cell division, mitochondria, including mtDNA, need to be accurately apportioned to daughter cells. This process requires an intimate and coordinated interplay between the cell cycle, mitochondrial dynamics and the replication and distribution of mtDNA. Recent years have seen exciting advances in the elucidation of the mechanisms that facilitate these processes and essential key players have been identified. Moreover, segregation of qualitatively distinct mitochondria during asymmetric cell division is emerging as an important quality control step, which secures the maintenance of a healthy cell population.
    Keywords:  asymmetric cell division; cell cycle; mammals; mitochondria; quality control; yeast
  7. J Biol Chem. 2019 Dec 09. pii: jbc.RA119.010998. [Epub ahead of print]
    Gong S, Wang X, Meng F, Cui L, Yi Q, Zhao Q, Cang X, Cai Z, Mo JQ, Liang Y, Guan MX.
      The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within the acceptor stem of mitochondrial tRNAHis  The primary defect in this mutation is an alteration in tRNAHis aminoacylation. Here, we further investigate the molecular mechanism of the deafness-associated tRNAHis 12201T>C mutation and test whether the overexpression of the human mitochondrial histidyl-tRNA synthetase gene (HARS2) in cytoplasmic hybrid (cybrid) cells carrying the m.12201T>C mutation reverses mitochondrial dysfunctions. Using molecular dynamics simulations, we demonstrate that the m.12201T>C mutation perturbs the tRNAHis structure and function, supported by decreased melting temperature, conformational changes and instability of mutated tRNA. We show that the m.12201T>C mutation-induced alteration of aminoacylation tRNAHis causes mitochondrial translational defects and respiratory deficiency. We found that the transfer of HARS2 into the cybrids carrying the m.12201T>C mutation raises the levels of aminoacylated tRNAHis from 56.3% to 75.0% but does not change the aminoacylation of other tRNAs. Strikingly, HARS2 overexpression increased the steady state levels of tRNAHis and of non-cognate tRNAs including tRNAAla, tRNAGln, tRNAGlu, tRNALeu(UUR), tRNALys and tRNAMet, in cells bearing the m.12201T>C mutation.  This improved tRNA metabolism elevated the efficiency of mitochondrial translation, activities of oxidative phosphorylation complexes and respiration capacity. Furthermore, HARS2 overexpression markedly increases mitochondrial ATP levels and membrane potential, and reduced production of reactive oxygen species in cells carrying the m.12201T>C mutation.  These results indicate that HARS2 overexpression corrects the mitochondrial dysfunction caused by the tRNAHis mutation. These findings provide critical insights into the pathophysiology of mitochondrial disease and represent a step toward improved therapeutic interventions for mitochondrial disorders.
    Keywords:  ATP; aminoacyl tRNA synthetase; aminoacylation; gene transfer; hearing; m.12201T>C mutation; mitochondrial DNA (mtDNA); mitochondrial histidyl-tRNA synthetase; mitochondrial membrane potential; mitochondrial respiratory chain complex; mitochondrial tRNA mutation; pathophysiology; reactive oxygen species (ROS); transfer RNA (tRNA); translation
  8. J Biochem. 2019 Dec 11. pii: mvz111. [Epub ahead of print]
    Eramo M, Lisnyak V, Formosa LE, Ryan MT.
      The "Mitochondrial Contact Site and Cristae Organising System" (MICOS) is an essential protein complex that promotes the formation, maintenance and stability of mitochondrial cristae. As such, loss of core MICOS components disrupts cristae structure and impairs mitochondrial function. Aberrant mitochondrial cristae morphology and diminished mitochondrial function is a pathological hallmark observed across many human diseases such as neurodegenerative conditions, obesity and diabetes mellitus, cardiomyopathy, and in muscular dystrophies and myopathies. While mitochondrial abnormalities are often an associated secondary effect to the pathological disease process, a direct role for the MICOS in health and human disease is emerging. This review describes the role of MICOS in the maintenance of mitochondrial architecture, and summarises both the direct and associated roles of the MICOS in human disease.
    Keywords:  MICOS; Mitochondria; cristae; membrane organisation
  9. Trends Mol Med. 2019 Dec 05. pii: S1471-4914(19)30298-9. [Epub ahead of print]
    Divakaruni AS, Murphy AN.
      Using an unbiased genetic screen, To et al. map genes that enhance or suppress growth defects in response to different mitochondrial inhibitors to model mitochondrial disease. The findings have novel implications for the interconnectivity of bioenergetic pathways, and suggest a provocative strategy to treat primary mitochondrial disorders.
    Keywords:  CRISPR screen; GPX4; complex I; mitochondrial toxins