bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2019‒12‒08
sixteen papers selected by
Gavin McStay
Staffordshire University

  1. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190187
    Klucnika A, Ma H.
      The animal mitochondrial genome, although small, can have a big impact on health and disease. Non-pathogenic sequence variation among mitochondrial DNA (mtDNA) haplotypes influences traits including fertility, healthspan and lifespan, whereas pathogenic mutations are linked to incurable mitochondrial diseases and other complex conditions like ageing, diabetes, cancer and neurodegeneration. However, we know very little about how mtDNA genetic variation contributes to phenotypic differences. Infrequent recombination, the multicopy nature and nucleic acid-impenetrable membranes present significant challenges that hamper our ability to precisely map mtDNA variants responsible for traits, and to genetically modify mtDNA so that we can isolate specific mutants and characterize their biochemical and physiological consequences. Here, we summarize the past struggles and efforts in developing systems to map and edit mtDNA. We also assess the future of performing forward and reverse genetic studies on animal mitochondrial genomes. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  genetic engineering; genotype to phenotype; linkage mapping; mitochondrial DNA
  2. Mol Genet Metab. 2019 Nov 21. pii: S1096-7192(19)30614-6. [Epub ahead of print]
    Protasoni M, Bruno C, Donati MA, Mohamoud K, Severino M, Allegri A, Robinson AJ, Reyes A, Zeviani M, Garone C.
      NUBPL (Nucleotide-binding protein like) protein encodes a member of the Mrp/NBP35 ATP-binding proteins family, deemed to be involved in mammalian complex I (CI) assembly process. Exome sequencing of a patient presenting with infantile-onset hepatopathy, renal tubular acidosis, developmental delay, short stature, leukoencephalopathy with minimal cerebellar involvement and multiple OXPHOS deficiencies revealed the presence of two novel pathogenic compound heterozygous variants in NUBPL (p.Phe242Leu/p.Leu104Pro). We investigated patient's and control immortalised fibroblasts and demonstrated that both the peripheral and the membrane arms of complex I are undetectable in mutant NUBPL cells, resulting in virtually absent CI holocomplex and loss of enzyme activity. In addition, complex III stability was moderately affected as well. Lentiviral-mediated expression of the wild-type NUBPL cDNA rescued both CI and CIII assembly defects, confirming the pathogenicity of the variants. In conclusion, this is the first report describing a complex multisystemic disorder due to NUBPL defect. In addition, we confirmed the role of NUBPL in Complex I assembly associated with secondary effect on Complex III stability and we demonstrated a defect of mtDNA-related translation which suggests a potential additional role of NUBPL in mtDNA expression.
    Keywords:  Brain MRI; Complex I assembly; Complex I assembly factors; Human complex I; Mitochondrial disorders; NUBPL
  3. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190176
    Knorre DA.
      Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent 'leakage' of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  epistasis; heterogeneity; heteroplasmy; mtDNA; selection; zygote
  4. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190169
    Ghiselli F, Milani L.
      Finding causal links between genotype and phenotype is a major issue in biology, even more in mitochondrial biology. First of all, mitochondria form complex networks, undergoing fission and fusion and we do not know how such dynamics influence the distribution of mtDNA variants across the mitochondrial network and how they affect the phenotype. Second, the non-Mendelian inheritance of mitochondrial genes can have sex-specific effects and the mechanism of mitochondrial inheritance is still poorly understood, so it is not clear how selection and/or drift act on mtDNA genetic variation in each generation. Third, we still do not know how mtDNA expression is regulated; there is growing evidence for a convoluted mechanism that includes RNA editing, mRNA stability/turnover, post-transcriptional and post-translational modifications. Fourth, mitochondrial activity differs across species as a result of several interacting processes such as drift, adaptation, genotype-by-environment interactions, mitonuclear coevolution and epistasis. This issue will cover several aspects of mitochondrial biology along the path from genotype to phenotype, and it is subdivided into four sections focusing on mitochondrial genetic variation, on the relationship among mitochondria, germ line and sex, on the role of mitochondria in adaptation and phenotypic plasticity, and on some future perspectives in mitochondrial research. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  heteroplasmy; mitochondrial bottleneck; mitochondrial expression manipulation; mitonuclear interactions; mtDNA editing; mtDNA genetic variation
  5. Mitochondrial DNA A DNA Mapp Seq Anal. 2019 Dec 04. 1-6
    Jahani MM, Azimi Meibody A, Karimi T, Banoei MM, Houshmand M.
      Breast cancer is the most common malignancy and the second leading cause of cancer deaths among women worldwide after lung cancer. Mitochondria play a central role in the regulation of cellular function, metabolism, and cell death in cancer cells. We aim to examine the mitochondrial polymorphisms of complex I in association with breast cancer in an Iranian cohort.This experimental study includes 53 patients with breast cancer and 35 healthy control patients. In addition, tumor-adjacent normal breast tissue was obtained from each patient. The DNA of the tissue cells was extracted and analyzed for complex I mutations using a PCR sequencing method. Our results show 94 mtDNA complex I variants in tumor tissues. A10398G was the most prevalent polymorphism and strongly correlated with Her2 receptor in tumor tissue samples. Mitochondrial DNA (mtDNA) mutations have been widely linked to the etiology of numerous disorders. The mtDNA mutations screening on A10398G along with other mutations might provide insight on the role of mitochondrial mutations in breast cancer.
    Keywords:  Breast cancer; complex I(ND1–ND6); mitochondria; mtDNA mutation
  6. Nucleic Acids Res. 2019 Dec 04. pii: gkz1128. [Epub ahead of print]
    Yim A, Koti P, Bonnard A, Marchiano F, Dürrbaum M, Garcia-Perez C, Villaveces J, Gamal S, Cardone G, Perocchi F, Storchova Z, Habermann BH.
      Mitochondria participate in metabolism and signaling. They adapt to the requirements of various cell types. Publicly available expression data permit to study expression dynamics of genes with mitochondrial function (mito-genes) in various cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for mito-genes. Here, we introduce the visual data mining platform mitoXplorer, which integrates expression and mutation data of mito-genes with a manually curated mitochondrial interactome containing ∼1200 genes grouped in 38 mitochondrial processes. User-friendly analysis and visualization tools allow to mine mitochondrial expression dynamics and mutations across various datasets from four model species including human. To test the predictive power of mitoXplorer, we quantify mito-gene expression dynamics in trisomy 21 cells, as mitochondrial defects are frequent in trisomy 21. We uncover remarkable differences in the regulation of the mitochondrial transcriptome and proteome in one of the trisomy 21 cell lines, caused by dysregulation of the mitochondrial ribosome and resulting in severe defects in oxidative phosphorylation. With the newly developed Fiji plugin mitoMorph, we identify mild changes in mitochondrial morphology in trisomy 21. Taken together, mitoXplorer ( is a user-friendly, web-based and freely accessible software, aiding experimental scientists to quantify mitochondrial expression dynamics.
  7. Ann Transl Med. 2019 Oct;7(20): 594
    Dasgupta S.
      Apart from reliable management of the "powerhouse" of the cell, mitochondria faithfully orchestrate a diverse array of important and critical functions in governing cellular signaling, apoptosis, autophagy, mitophagy and innate and adaptive immune system. Introduction of instability and imbalance in the mitochondrial own genome or the nuclear encoded mitochondrial proteome would result in the manifestation of various diseases through alterations in the oxidative phosphorylation system (OXPHOS) and nuclear-mitochondria retrograde signaling. Understanding mitochondrial biology and dynamism are thus of paramount importance to develop strategies to prevent or treat various diseases caused due to mitochondrial alterations.
    Keywords:  Mitochondria; biomarker; cancer; genetic disorders; therapy
  8. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190173
    Schaack S, Ho EKH, Macrae F.
      Understanding and quantifying the rates of change in the mitochondrial genome is a major component of many areas of biological inquiry, from phylogenetics to human health. A critical parameter in understanding rates of change is estimating the mitochondrial mutation rate (mtDNA MR). Although the first direct estimates of mtDNA MRs were reported almost 20 years ago, the number of estimates has not grown markedly since that time. This is largely owing to the challenges associated with time- and labour-intensive mutation accumulation (MA) experiments. But even MA experiments do not solve a major problem with estimating mtDNA MRs-the challenge of disentangling the role of mutation from other evolutionary forces acting within the cell. Now that it is widely understood that any newly generated mutant allele in the mitochondria will initially be at very low frequency (1/N, where N is the number of mtDNA molecules in the cell), the importance of understanding the effective population size (Ne) of the mtDNA and the size of genetic bottlenecks during gametogenesis and development has come into the spotlight. In addition to these factors regulating the role of genetic drift, advances in our understanding of mitochondrial replication and turnover allow us to more easily envision how natural selection within the cell might favour or purge mutations in multi-copy organellar genomes. Here, we review the unique features of the mitochondrial genome that pose a challenge for accurate MR estimation and discuss ways to overcome those challenges. Estimates of mtDNA MRs remain one of the most widely used parameters in biology, thus accurate quantification and a deeper understanding of how and why they may vary within and between individuals, populations and species is an important goal. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  effective population size; genetic bottleneck; heteroplasmy; mtDNA; mutation accumulation; mutation rate
  9. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190174
    Dubie JJ, Caraway AR, Stout MM, Katju V, Bergthorsson U.
      Mitochondrial genomes can sustain mutations that are simultaneously detrimental to individual fitness and yet, can proliferate within individuals owing to a replicative advantage. We analysed the fitness effects and population dynamics of a mitochondrial genome containing a novel 499 bp deletion in the cytochrome b(1) (ctb-1) gene (Δctb-1) encoding the cytochrome b of complex III in Caenorhabditis elegans. Δctb-1 reached a high heteroplasmic frequency of 96% in one experimental line during a mutation accumulation experiment and was linked to additional spontaneous mutations in nd5 and tRNA-Asn. The Δctb-1 mutant mitotype imposed a significant fitness cost including a 65% and 52% reduction in productivity and competitive fitness, respectively, relative to individuals bearing wild-type (WT) mitochondria. Deletion-bearing worms were rapidly purged within a few generations when competed against WT mitochondrial DNA (mtDNA) bearing worms in experimental populations. By contrast, the Δctb-1 mitotype was able to persist in large populations comprising heteroplasmic individuals only, although the average intracellular frequency of Δctb-1 exhibited a slow decline owing to competition among individuals bearing different frequencies of the heteroplasmy. Within experimental lines subjected to severe population bottlenecks (n = 1), the relative intracellular frequency of Δctb-1 increased, which is a hallmark of selfish drive. A positive correlation between Δctb-1 and WT mtDNA copy-number suggests a mechanism that increases total mtDNA per se, and does not discern the Δctb-1 mitotype from the WT mtDNA. This study demonstrates the selfish nature of the Δctb-1 mitotype, given its transmission advantage and substantial fitness load for the host, and highlights the importance of population size for the population dynamics of selfish mtDNA. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  fitness; genomic conflict; heteroplasmy; mitochondrial deletion; selection; selfish genetic element
  10. Biomed Rep. 2019 Dec;11(6): 257-268
    Alharbi MA, Al-Kafaji G, Khalaf NB, Messaoudi SA, Taha S, Daif A, Bakhiet M.
      Multiple sclerosis (MS) is an immune-mediated neurological, inflammatory disease of the central nervous system. Recent studies have suggested that genetic variants in mitochondrial DNA (mtDNA)-encoded complexes of respiratory chain, particularly, complex I (NADH dehydrogenase), contribute to the pathogenicity of MS among different ethnicities, and targeting mitochondrial function may represent a novel approach for MS therapy. In this study, we sequenced ND genes (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6) encoding subunits of complex I in 124 subjects, 60 patients with relapsing-remitting MS and 64 healthy individuals, in order to identify potential novel mutations in these patients. We found several variants in ND genes in both the patients and controls, and specific variants only in patients with MS. While the majority of these variants were synonymous, 4 variants in the ND4 gene were identified as missense mutations in patients with MS. Of these, m.11150G>A was observed in one patient, whereas m.11519A>C, m.11523A>C and m.11527C>T were observed in another patient. Functional analysis predicted the mutations, m.11519A>C, m.11523A>C and m.11150G>A, as deleterious with a direct impact on ND4 protein stability and complex I function, whereas m.11527C>T mutation had no effect on ND4 protein stability. However, the 3 mutations, m.11519A>C, m.11523A>C and m.11527C>T, which were observed in the same patient, were predicted to cause a cumulative destabilizing effect on ND4 protein, and could thus disrupt complex I function. On the whole, this study identified 4 novel mutations in the mtDNA-encoded ND4 gene in patients with MS, which could lead to complex I dysfunction, and further confirmed the implication of mtDNA mutations in the pathogenicity of MS. The identified novel mutations in patients with MS may be ethnic-related and may prove to be significant in personalized treatment.
    Keywords:  complex I; gene mutations; mitochondrial DNA; multiple sclerosis
  11. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190185
    Wallis CP, Scott LH, Filipovska A, Rackham O.
      Many conventional, modern genome engineering tools cannot be used to study mitochondrial genetics due to the unusual structure and physiology of the mitochondrial genome. Here, we review a number of newly developed, synthetic biology-based approaches for altering levels of mutant mammalian mitochondrial DNA and mitochondrial RNAs, including transcription activator-like effector nucleases, zinc finger nucleases and engineered RNA-binding proteins. These approaches allow researchers to manipulate and visualize mitochondrial processes and may provide future therapeutics. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  mitochondria; mitochondrial disease; mitochondrial restriction enzymes; mitochondrial transcription activator-life effectors nucleases; mitochondrial zinc finger nucleases; synthetic biology
  12. Biochem Biophys Rep. 2019 Dec;20 100710
    Vekshin N, Kovalev V, Chaplygina A.
      A number of properties of the smallest (less than 0.2 μm) germinal proto-mitochondria (PRMC) from rat liver have been studied. These PRMC were obtained by filtering the light fraction of hepatic mitochondria (MC) through calibrated millipore membranes. Germinal PRMC contain in general the same proteins as MC. However, they have the reduced content of flavoproteins and zero cytochrome oxidase. Germinal PRMC, in contrast to MC, almost does not contain the "aging pigment" - lipofuscin. They have DNA; the DNA/protein ratio in them is much higher than in MC, i.e. they are poor in protein. The obtained results support the earlier assumption that MC in specialized animal cells can arise from germinal PRMC - particles smaller than 0.2 μm containing DNA. It is assumed that the DNA molecules enter to cytoplasm during degradation of old MC serves as a seed for the formation of PRMC (with the connection of nuclear DNA).
    Keywords:  Flavoproteins; Lipofuscin; MC, mitochondria; Mitochondria; Mitochondrial DNA; PRMC, protomitochondria; Post-mitochondria; Proto-mitochondria; Respiratory chain
  13. Mol Genet Metab Rep. 2019 Dec;21 100543
    Fragaki K, Chaussenot A, Serre V, Acquaviva C, Bannwarth S, Rouzier C, Chabrol B, Paquis-Flucklinger V.
      Among mitochondrial diseases, isolated complex V (CV) deficiency represents a rare cause of respiratory chain (RC) dysfunction. In mammalian mitochondrial DNA (mtDNA), MT-ATP6 partly overlaps with MT-ATP8 making double mutations possible, yet extremely rarely reported principally in patients with cardiomyopathy. Here, we report a novel m.8561 C>T substitution in the overlapping region of MT-ATP6 and MT-ATP8 in a child with early-onset ataxia, psychomotor delay and microcephaly, enlarging the clinical manifestations spectrum associated with CV deficiency.
    Keywords:  ADP, adenosine triphosphate; ATP synthase; ATP, adenosine triphosphate; Ataxia; BN-PAGE, Blue Native-PolyAcrylamide Gel Electrophoresis; CV, complex V; MRI, Magnetic resonance imaging; Microcephaly; Mitochondrial disorders; NARP, Neuropathy, Ataxia, Retinitis Pigmentosa; NGS, Next-generation sequencing; OXPHOS, oxidative phosphorylation; PCR, polymerase chain reaction; PVDF, PolyVinyliDene Fluoride; Psychomotor delay; RC, respiratory chain; RFLP, Restriction Fragment Length Polymorphism; WT, wild-type; mtDNA, mitochondrial DNA
  14. Philos Trans R Soc Lond B Biol Sci. 2020 Jan 20. 375(1790): 20190186
    Milani L, Ghiselli F.
      Inference from model organisms has been the engine for many discoveries in life science, but indiscriminate generalization leads to oversimplifications and misconceptions. Model organisms and inductive reasoning are irreplaceable: there is no other way to tackle the complexity of living systems. At the same time, it is not advisable to infer general patterns from a restricted number of species, which are very far from being representative of the diversity of life. Not all models are equal. Some organisms are suitable to find similarities across species, other highly specialized organisms can be used to focus on differences. In this opinion piece, we discuss the dominance of the mechanistic/reductionist approach in life sciences and make a case for an enhanced application of the comparative approach to study processes in all their various forms across different organisms. We also enlist some rising animal models in mitochondrial research, to exemplify how non-model organisms can be chosen in a comparative framework. These taxa often do not possess implemented tools and dedicated methods/resources. However, because of specific features, they have the potential to address still unanswered biological questions. Finally, we discuss future perspectives and caveats of the comparative method in the age of 'big data'. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
    Keywords:  comparative biology; generalization; idiographics; mitochondria; nomothetics; non-model organisms
  15. Biogerontology. 2019 Dec 04.
    Whitehall JC, Greaves LC.
      Alterations in mitochondrial metabolism have been described as one of the major hallmarks of both ageing cells and cancer. Age is the biggest risk factor for the development of a significant number of cancer types and this therefore raises the question of whether there is a link between age-related mitochondrial dysfunction and the advantageous changes in mitochondrial metabolism prevalent in cancer cells. A common underlying feature of both ageing and cancer cells is the presence of somatic mutations of the mitochondrial genome (mtDNA) which we postulate may drive compensatory alterations in mitochondrial metabolism that are advantageous for tumour growth. In this review, we discuss basic mitochondrial functions, mechanisms of mtDNA mutagenesis and their metabolic consequences, and review the evidence for and against a role for mtDNA mutations in cancer development.
    Keywords:  Ageing; Cancer; Metabolism; Mitochondria; mtDNA mutations
  16. Mol Genet Metab Rep. 2019 Dec;21 100541
    Finsterer J.
    Keywords:  Heteroplasmy; Mitochondrial disorder; Multisystem; Respiratory chain; Stroke-like episode; mtDNA