bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒05‒03
three papers selected by
Gavin McStay
Staffordshire University


  1. Neurobiol Dis. 2020 Apr 25. pii: S0969-9961(20)30155-8. [Epub ahead of print] 104880
    Nottia MD, Marchese M, Verrigni D, Mutti C, Torraco A, Oliva R, Fernandez-Vizarra E, Morani F, Trani G, Rizza T, Ghezzi D, Ardissone A, Nesti C, Vasco G, Zeviani M, Minczuk M, Bertini E, Santorelli FM, Carrozzo R.
      Mitochondrial ribosomal protein large 24 (MRPL24) is 1 of the 82 protein components of mitochondrial ribosomes, playing an essential role in the mitochondrial translation process. We report here on a baby girl with cerebellar atrophy, choreoathetosis of limbs and face, intellectual disability and a combined defect of complexes I and IV in muscle biopsy, caused by a homozygous missense mutation identified in MRPL24. The variant predicts a Leu91Pro substitution at an evolutionarily conserved site. Using human mutant cells and the zebrafish model, we demonstrated the pathological role of the identified variant. In fact, in fibroblasts we observed a significant reduction of MRPL24 protein and of mitochondrial respiratory chain complex I and IV subunits, as well a markedly reduced synthesis of the mtDNA-encoded peptides. In zebrafish we demonstrated that the orthologue gene is expressed in metabolically active tissues, and that gene knockdown induced locomotion impairment, structural defects and low ATP production. The motor phenotype was complemented by human WT but not mutant cRNA. Moreover, sucrose density gradient fractionation showed perturbed assembly of large subunit mitoribosomal proteins, suggesting that the mutation leads to a conformational change in MRPL24, which is expected to cause an aberrant interaction of the protein with other components of the 39S mitoribosomal subunit.
    Keywords:  MRPL24; Mitochondrial disorders; Mitochondrial protein synthesis; Mitoribosomes; Molecular modeling; Movement disorder; Protein interactions; Zebrafish
    DOI:  https://doi.org/10.1016/j.nbd.2020.104880
  2. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 26. pii: S0925-4439(20)30148-4. [Epub ahead of print] 165803
    Bertero E, Kutschka I, Maack C, Dudek J.
      Mitochondria play a prominent role in cardiac energy metabolism, and their function is critically dependent on the integrity of mitochondrial membranes. Disorders characterized by mitochondrial dysfunction are commonly associated with cardiac disease. The mitochondrial phospholipid cardiolipin directly interacts with a number of essential protein complexes in the mitochondrial membranes including the respiratory chain, mitochondrial metabolite carriers, and proteins critical for mitochondrial morphology. Barth syndrome is an X-linked disorder caused by an inherited defect in the biogenesis of the mitochondrial phospholipid cardiolipin. How cardiolipin deficiency impacts on mitochondrial function and how mitochondrial dysfunction causes cardiomyopathy has been intensively studied in cellular and animal models of Barth syndrome. These findings may also have implications for the molecular mechanisms underlying other inherited disorders associated with defects in cardiolipin, like Sengers syndrome and dilated cardiomyopathy with ataxia (DCMA).
    Keywords:  Barth syndrome; Cardiolipin; Dilated cardiomyopathy with ataxia; Mitochondria; Mitochondriopathies; Respiratory chain; Sengers syndrome
    DOI:  https://doi.org/10.1016/j.bbadis.2020.165803
  3. Biochim Biophys Acta Bioenerg. 2020 Apr 23. pii: S0005-2728(20)30063-3. [Epub ahead of print] 148213
    Adjobo-Hermans MJW, de Haas R, Willems PHGM, Wojtala A, van Emst-de Vries SE, Wagenaars JA, van den Brand M, Rodenburg RJ, Smeitink JAM, Nijtmans LG, Sazanov LA, Wieckowski MR, Koopman WJH.
      Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4-/- mouse tissues. Ndufs4-/- animals displayed significantly lower CI subunit levels in brain/diaphragm relative to other tissues (liver/heart/kidney/skeletal muscle), whereas other OXPHOS subunit levels were not reduced. Absence of NDUFS4 induced near complete absence of the NDUFA12 accessory subunit, a 50% reduction in other CI subunit levels, and an increase in specific CI assembly factors. Among the latter, NDUFAF2 was most highly increased. Regarding NDUFS4, NDUFA12 and NDUFAF2, identical results were obtained in Ndufs4-/- mouse embryonic fibroblasts (MEFs) and NDUFS4-mutated LS patient cells. Ndufs4-/- MEFs contained active CI in situ but blue-native-PAGE highlighted that NDUFAF2 attached to an inactive CI subcomplex (CI-830) and inactive assemblies of higher MW. In NDUFA12-mutated LS patient cells, NDUFA12 absence did not reduce NDUFS4 levels but triggered NDUFAF2 association to active CI. BN-PAGE revealed no such association in LS patient fibroblasts with mutations in other CI subunit-encoding genes where NDUFAF2 was attached to CI-830 (NDUFS1, NDUFV1 mutation) or not detected (NDUFS7 mutation). Supported by enzymological and CI in silico structural analysis, we conclude that absence of NDUFS4 induces near complete absence of NDUFA12 but not vice versa, and that NDUFAF2 stabilizes active CI in Ndufs4-/- mice and LS patient cells, perhaps in concert with mitochondrial inner membrane lipids.
    Keywords:  Fibroblasts; Leigh syndrome; NADH:ubiquinone oxidoreductase; Proteomics
    DOI:  https://doi.org/10.1016/j.bbabio.2020.148213