bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒05‒24
six papers selected by
Gavin McStay
Staffordshire University
  1. A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome.
  2. An Unusual Amino Acid Substitution Within Hummingbird Cytochrome c Oxidase Alters a Key Proton-Conducting Channel.
  3. Mitochondrial Protein Quality Control Mechanisms.
  4. Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.
  5. The rise and rise of mitochondrial DNA mutations.
  6. G6036A substitution in mitochondrial COX I gene compromises cytochrome c oxidase activity in thiamine responsive Leigh syndrome patients.
  1. Clin Chem Lab Med. 2020 May 20. pii: /j/cclm.ahead-of-print/cclm-2020-0150/cclm-2020-0150.xml. [Epub ahead of print]
    A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome.
    Miaomiao Du, Xiujuan Wei, Pu Xu, Anran Xie, Xiyue Zhou, Yanling Yang, Dongxiao Li, Jianxin Lyu, Hezhi Fang.
      Objectives Leigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete. Methods Next-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant. Results A novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells. Conclusions A novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.
    Keywords:  Leigh syndrome; complex I deficiency; m.14430A>G (MT-ND6, p.W82R); mitochondrial diseases
    DOI:  https://doi.org/10.1515/cclm-2020-0150
  2. G3 (Bethesda). 2020 May 22. pii: g3.401312.2020. [Epub ahead of print]
    An Unusual Amino Acid Substitution Within Hummingbird Cytochrome c Oxidase Alters a Key Proton-Conducting Channel.
    Cory D Dunn, Bala A Akpinar, Vivek Sharma.
      Hummingbirds in flight exhibit the highest mass-specific metabolic rate of all vertebrates. The bioenergetic requirements associated with sustained hovering flight raise the possibility of unique amino acid substitutions that would enhance aerobic metabolism. Here, we have identified a non-conservative substitution within the mitochondria-encoded cytochrome c oxidase subunit I (COI) that is fixed within hummingbirds, but not among other vertebrates. This unusual change is also rare among metazoans, but can be identified in several clades with diverse life histories. We performed atomistic molecular dynamics simulations using bovine and hummingbird COI models, thereby bypassing experimental limitations imposed by the inability to modify mtDNA in a site-specific manner. Intriguingly, our findings suggest that COI amino acid position 153 (bovine numbering system) provides control over the hydration and activity of a key proton channel in COX. We discuss potential phenotypic outcomes linked to this alteration encoded by hummingbird mitochondrial genomes.
    Keywords:  bioenergetics; cytochrome c oxidase; hummingbird; mtDNA; phylogenetics
    DOI:  https://doi.org/10.1534/g3.120.401312
  3. Genes (Basel). 2020 May 18. pii: E563. [Epub ahead of print]11(5):
    Mitochondrial Protein Quality Control Mechanisms.
    Pooja Jadiya, Dhanendra Tomar.
      Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.
    Keywords:  chaperones; mitochondria; mitochondria-associated degradation; mitochondrial protein quality control; mitochondrial unfolded protein response; mitophagy; protease; proteasome; proteome; ubiquitin
    DOI:  https://doi.org/10.3390/genes11050563
  4. J Neuromuscul Dis. 2020 May 16.
    Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.
    Yavuz Oktay, Serdal Güngör, Lena Zeltner, Sarah Wiethoff, Ludger Schöls, Ece Sonmezler, Elmasnur Yilmaz, Benjamin Munro, Benjamin Bender, Christoph Kernstock, Sofie Kaemereit, Inga Liepelt, Ana Töpf, Uluc Yis, Steven Laurie, Ahmet Yaramis, Stephan Zuchner, Semra Hiz, Hanns Lochmüller, Rebecca Schüle, Rita Horvath.
      BACKGROUND: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease.OBJECTIVE: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype.
    METHODS: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families.
    RESULTS: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15).
    CONCLUSIONS: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.
    DOI:  https://doi.org/10.3233/JND-200510
  5. Open Biol. 2020 May;10(5): 200061
    The rise and rise of mitochondrial DNA mutations.
    Conor Lawless, Laura Greaves, Amy K Reeve, Doug M Turnbull, Amy E Vincent.
      How mitochondrial DNA mutations clonally expand in an individual cell is a question that has perplexed mitochondrial biologists for decades. A growing body of literature indicates that mitochondrial DNA mutations play a major role in ageing, metabolic diseases, neurodegenerative diseases, neuromuscular disorders and cancers. Importantly, this process of clonal expansion occurs for both inherited and somatic mitochondrial DNA mutations. To complicate matters further there are fundamental differences between mitochondrial DNA point mutations and deletions, and between mitotic and post-mitotic cells, that impact this pathogenic process. These differences, along with the challenges of investigating a longitudinal process occurring over decades in humans, have so far hindered progress towards understanding clonal expansion. Here we summarize our current understanding of the clonal expansion of mitochondrial DNA mutations in different tissues and highlight key unanswered questions. We then discuss the various existing biological models, along with their advantages and disadvantages. Finally, we explore what has been achieved with mathematical modelling so far and suggest future work to advance this important area of research.
    Keywords:  ageing; clonal expansion; disease; heteroplasmy; mtDNA; mutation
    DOI:  https://doi.org/10.1098/rsob.200061
  6. J Neurol Sci. 2020 Apr 30. pii: S0022-510X(20)30206-9. [Epub ahead of print]415 116870
    G6036A substitution in mitochondrial COX I gene compromises cytochrome c oxidase activity in thiamine responsive Leigh syndrome patients.
    Shalini Mani, S Narasimha Rao, M V Kranthi Kumar.
      Cytochrome c oxidase (COX) deficiency is known to be associated with Leigh syndrome (LS), however there are limited studies on genetic screening of mitochondrial (mt) DNA encoding COX genes as well as the functional validation of identified variants. In our previous studies, we cared for total 165 LS patients and analyzed the nucleotide variations across entire mt genome. We observed a high level of genetic heterogeneity in these patients. We identified various reported and novel variation across entire genome including COX genes. In our present study we have further studied and functionally validated the selected novel nucleotide variant of COX I and COX II gene using different in-silico tools and trans mitochondrial cybrid based assays. As a result of our study, G6036A (G45S) variant of COX I gene, reduced the COX activity in both spectrophotometric as well as In-gel BN-PAGE assays. FACS analysis also revealed this variant to affect the mitochondrial membrane potential in the respective cybrids. Interestingly most of our in-silico studies indicated that this variant might affect the secondary structure and confirmation of COX I protein. Thus we report the first missense mutation in the COX I gene of LS patients and justify its pathogenic role in these patients by different assays. Variant A7746G (N54K) in COX II gene was also predicted to affect the secondary structure as well as stability of COX II protein. Though, the effect of this variant was not significant, however it will be interesting to investigate its significance by other assays in future.
    Keywords:  Blue-Native PAGE; COX I; COX II; Cytochrome c oxidase; In-silico; Leigh syndrome
    DOI:  https://doi.org/10.1016/j.jns.2020.116870
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