bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2019‒11‒10
nine papers selected by
Gavin McStay
Staffordshire University


  1. J Pediatr Genet. 2019 Dec;8(4): 231-234
    Vázquez-Justes D, Carreño-Gago L, García-Arumi E, Traveset A, Montoya J, Ruiz-Pesini E, López R, Brieva L.
      This article reports a Leber hereditary optic neuropathy (LHON) case associated for the first time with mitochondrial m.13513G>A mutation. We present a 16-year-old man who complained of subacute, painless, visual loss. Ocular examination showed optic nerve atrophy, papillary pseudoedema, and optic disc pallor. Extraocular manifestations included hypertrophic myocardiopathy and myopathy. Initial genetic analysis excluded the three most common LHON mutations. Sanger sequencing of the whole mitochondrial deoxyribonucleic acid showed no mutation. Next-generation sequencing (NGS) revealed m.13513G>A mutation in the NADH dehydrogenase (ND5) subunit gene ( MT-ND5 ). The m.13513G>A mutation has never been associated with LHON phenotype without Leigh/mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes features. NGS techniques should be considered when this diagnosis is strongly suspected.
    Keywords:  Leber hereditary optic neuropathy; next-generation sequencing; whole genome sequencing
    DOI:  https://doi.org/10.1055/s-0039-1691812
  2. Endocr Pract. 2019 Nov 04.
    Robinson KN, Terrazas S, Giordano-Mooga S, Xavier NA.
      OBJECTIVE: Maternally Inherited Diabetes and Deafness (MIDD) is a rare diabetic syndrome mainly caused by a point mutation in the mitochondrial DNA (mtDNA), mt3243 A>G. The objective of this paper is to review the genetic inheritance, the clinical manifestations and the treatment of patients with MIDD.METHODS: The current review used a literature search of scientific papers on this rare syndrome.
    RESULTS: MtDNA is primarily inherited through the maternal oocyte, therefore the genetic abnormalities in MIDD are associated with maternal inheritance. Mitochondria contain circular mtDNA which codes for various mitochondrial genes. The mtDNA can be heteroplasmic, containing more than one type of mtDNA sequence; if one of the mtDNAs contains the mt3243A>G mutation, a patient may develop MIDD. Patients can inherit different amounts of mutated mtDNA and normal mtDNA that effect the severity of the clinical manifestations of MIDD. The most common clinical manifestations include diabetes mellitus (DM), deafness, ophthalmic disease, cardiac disease, renal disease, gastrointestinal disease, short stature, and myopathies. In order to effectively treat patients with MIDD it is important to recognize the underlying pathophysiology of this specific form of diabetes and the pathophysiology associated with the organ-specific complications present in this disease.
    CONCLUSION: The heteroplasmic inheritance of mutated mtDNA play an important role in the clinical manifestations of various mitochondrial diseases, specifically MIDD. This review will alert endocrinologists of the signs and symptoms of MIDD patients and important clinical considerations when managing this disease.
    DOI:  https://doi.org/10.4158/EP-2019-0270
  3. Cell Rep. 2019 Nov 05. pii: S2211-1247(19)31284-7. [Epub ahead of print]29(6): 1728-1738.e9
    Busch JD, Cipullo M, Atanassov I, Bratic A, Silva Ramos E, Schöndorf T, Li X, Pearce SF, Milenkovic D, Rorbach J, Larsson NG.
      Mitochondria harbor specialized ribosomes (mitoribosomes) necessary for the synthesis of key membrane proteins of the oxidative phosphorylation (OXPHOS) machinery located in the mitochondrial inner membrane. To date, no animal model exists to study mitoribosome composition and mitochondrial translation coordination in mammals in vivo. Here, we create MitoRibo-Tag mice as a tool enabling affinity purification and proteomics analyses of mitoribosomes and their interactome in different tissues. We also define the composition of an assembly intermediate formed in the absence of MTERF4, necessary for a late step in mitoribosomal biogenesis. We identify the orphan protein PUSL1, which interacts with a large subunit assembly intermediate, and demonstrate that it is an inner-membrane-associated mitochondrial matrix protein required for efficient mitochondrial translation. This work establishes MitoRibo-Tag mice as a powerful tool to study mitoribosomes in vivo, enabling future studies on the mitoribosome interactome under different physiological states, as well as in disease and aging.
    Keywords:  MitoRibo-Tag mice; OXPHOS; in vivo mouse model; mitochondria; mitochondrial DNA; mitochondrial biogenesis; mitochondrial gene expression; mitochondrial ribosome; ribosome; translation
    DOI:  https://doi.org/10.1016/j.celrep.2019.09.080
  4. J Biol Chem. 2019 Nov 04. pii: jbc.RA119.010598. [Epub ahead of print]
    Fan W, Zheng J, Kong W, Cui L, Aishanjiang M, Yi Q, Wang M, Cang X, Tang X, Chen Y, Mo JQ, Sondheimer N, Ge W, Guan MX.
      Nuclear modifier genes have been proposed to modify the phenotypic expression of mitochondrial DNA mutations. Using a targeted exome sequencing approach, here we found that the p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) interacts with the tRNASer(UCN) 7511A>G mutation in causing deafness. Strikingly, members of a Chinese family bearing both YARS2 p.191Gly>Val and m.7511A>G mutations displayed much higher penetrance of deafness than those pedigrees carrying only the m.7511A>G mutation. The m.7511A>G mutation changed the A4:U69 base pairing to G4:U69 pairing at the aminoacyl acceptor stem of tRNASer(UCN) and perturbed tRNASer(UCN) structure and function, including an increased melting temperature, altered conformation, instability, and aberrant aminoacylation of mutant tRNA. Using lymphoblastoid cell lines derived from symptomatic and asymptomatic members of these Chinese families and control subjects, we show that cell lines harboring only the m.7511A>G or p.191Gly>Val mutation revealed relatively mild defects in tRNASer(UCN) or tRNATyr metabolism, respectively. However, cell lines harboring both m.7511A>G and p.191Gly>Val mutations displayed more severe defective aminoacylations and lower tRNASer(UCN) and tRNATyr levels, aberrant aminoacylation, and lower levels of other tRNAs, including tRNAThr, tRNALys, tRNALeu(UUR), and tRNASer(AGY), than those in the cell lines carrying only the m.7511A>G or p.191Gly>Val mutation. Furthermore, mutant cell lines harboring both m.7511A>G and p.191Gly>Val mutations exhibited greater decreases in the levels of mitochondrial translation, respiration, and mitochondrial ATP and membrane potentials, along with increased production of reactive oxygen species. Our findings provide molecular-level insights into the pathophysiology of maternally transmitted deafness arising from the synergy between tRNASer(UCN) and mitochondrial YARS mutations.
    Keywords:  RNA metabolism; hearing; maternal inheritance; mitochondrial DNA (mtDNA); mitochondrial disease; mitochondrial metabolism; mitochondrial respiratory chain complex; mitochondrial translation; mutation; pathogenesis; reactive oxygen species (ROS); synergy; transfer RNA (tRNA); translation; tyrosyl-tRNA synthetase
    DOI:  https://doi.org/10.1074/jbc.RA119.010598
  5. PLoS One. 2019 ;14(11): e0224132
    Bénit P, Kahn A, Chretien D, Bortoli S, Huc L, Schiff M, Gimenez-Roqueplo AP, Favier J, Gressens P, Rak M, Rustin P.
      Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. We first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested, albeit with varying IC50 values, generally in the micromolar range. In addition to SDH, we observed that five of the SDHIs, mostly from the latest generation, inhibit the activity of RC complex III. Finally, we show that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer's disease).
    DOI:  https://doi.org/10.1371/journal.pone.0224132
  6. Yeast. 2019 Nov 05.
    Dujon B.
      Mitochondrial genetics started decades ago with the discovery of yeast mutants that ignored the mendelian rules of inheritance. Today, the many known DNA sequences of this second eukaryotic genome illustrate its eccentricity in terms of informational content and functional organization, suggesting a yet incomplete understanding of its evolution. The hereditary transmission of mitochondrial alleles relies on complex mixes of molecular and cellular mechanisms in which recombination and limited sampling, two sources of rapid genetic changes, play central roles. It is also under the influence of invasive genetic elements whose inconstant distribution in mitochondrial genomes suggests rapid turnovers in evolving populations. This susceptibility to changes contrasts with the development of specific functional interactions between the mitochondrial and nuclear genetic compartments, a trend that is prone to limit the genetic exchanges between distinct lineages. It is perhaps this opposition and the discordant inheritance between mitochondrial and nuclear genomes that best explain the maintenance of a second genome and a second independent protein synthesizing machinery in eukaryotic cells.
    Keywords:  concatemers; evolution; incompatibility; intron-homing; recombination; yeast
    DOI:  https://doi.org/10.1002/yea.3445
  7. Mitochondrion. 2019 Oct 31. pii: S1567-7249(19)30078-9. [Epub ahead of print]
    Varhaug KN, Kråkenes T, Alme MN, Vedeler CA, Bindoff LA.
      BACKGROUND: Cuprizone administration in mice leads to oligodendrocyte death and demyelination. The effect is thought to reflect copper-chelation that leads to inhibition of complex IV of the mitochondrial respiratory chain. The effects this drug has on neurons are less well known.OBJECTIVE: To investigate the toxic effects of cuprizone on mitochondria in neurons.
    METHODS: Male c57Bl/6 mice were fed 0.2% cuprizone for up to 5 weeks. Cuprizone-fed and control mice were examined at week 1, 3, 5 and 4 weeks after cessation of cuprizone exposure. The brain was examined for myelin, complex I, complex IV and for COX/SDH activities. Mitochondrial-DNA was investigated for deletions and copy number variation.
    RESULTS: We found decreased levels of complex IV in the cerebellar Purkinje neurons of mice exposed to cuprizone. This decrease was not related to a general decrease in mitochondrial volume or mass, as there were no differences in the levels of complex I or TOMM20.
    CONCLUSION: Neurons are affected by cuprizone-treatment. Whether this mitochondrial dysfunction acts as a subclinical trigger for demyelination and the long-term axonal degeneration that proceeds after cuprizone treatment stops remains unclear.
    Keywords:  complex IV; cuprizone; mitochondria; mitochondrial-DNA; multiple sclerosis; neurodegeneration
    DOI:  https://doi.org/10.1016/j.mito.2019.09.003
  8. Nature. 2019 Nov 06.
    MacVicar T, Ohba Y, Nolte H, Mayer FC, Tatsuta T, Sprenger HG, Lindner B, Zhao Y, Li J, Bruns C, Krüger M, Habich M, Riemer J, Schwarzer R, Pasparakis M, Henschke S, Brüning JC, Zamboni N, Langer T.
      Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis1-3. Here we show that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts. Similar changes to the mitochondrial proteome occur in the tumour tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumours. Our results identify the mTORC1-LIPIN1-YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41586-019-1738-6
  9. J Enzyme Inhib Med Chem. 2020 Dec;35(1): 129-137
    Cirigliano A, Amelina A, Biferali B, Macone A, Mozzetta C, Bianchi MM, Mori M, Botta B, Pick E, Negri R, Rinaldi T.
      The 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme of the mevalonate pathway for the synthesis of cholesterol in mammals (ergosterol in fungi), is inhibited by statins, a class of cholesterol lowering drugs. Indeed, statins are in a wide medical use, yet statins treatment could induce side effects as hepatotoxicity and myopathy in patients. We used Saccharomyces cerevisiae as a model to investigate the effects of statins on mitochondria. We demonstrate that statins are active in S.cerevisiae by lowering the ergosterol content in cells and interfering with the attachment of mitochondrial DNA to the inner mitochondrial membrane. Experiments on murine myoblasts confirmed these results in mammals. We propose that the instability of mitochondrial DNA is an early indirect target of statins.
    Keywords:  Statins; cholesterol; ergosterol; mitochondrial DNA; myopathy
    DOI:  https://doi.org/10.1080/14756366.2019.1687461