bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒01‒05
four papers selected by
Gavin McStay
Staffordshire University


  1. Mol Cell. 2019 Dec 20. pii: S1097-2765(19)30867-6. [Epub ahead of print]
    Salvatori R, Kehrein K, Singh AP, Aftab W, Möller-Hergt BV, Forne I, Imhof A, Ott M.
      The mitochondrial oxidative phosphorylation system comprises complexes assembled from subunits derived from mitochondrial and nuclear gene expression. Both genetic systems are coordinated by feedback loops, which control the synthesis of specific mitochondrial encoded subunits. Here, we studied how this occurs in the case of cytochrome b, a key subunit of mitochondrial complex III. Our data suggest the presence of a molecular rheostat consisting of two translational activators, Cbp3-Cbp6 and Cbs1, which operates at the mitoribosomal tunnel exit to connect translational output with assembly efficiency. When Cbp3-Cbp6 is engaged in assembly of cytochrome b, Cbs1 binds to the tunnel exit to sequester the cytochrome b-encoding mRNA, repressing its translation. After mediating complex III assembly, binding of Cbp3-Cbp6 to the tunnel exit replaces Cbs1 and the bound mRNA to permit cytochrome b synthesis. Collectively, the data indicate the molecular wiring of a feedback loop to regulate synthesis of a mitochondrial encoded protein.
    Keywords:  Mitochondrial biogenesis; mitochondrial gene expression; mitochondrial ribosome; mitoribosome interactors; respiratory chain assembly; ribosomal tunnel exit; translation activation; translation regulation
    DOI:  https://doi.org/10.1016/j.molcel.2019.11.019
  2. J Cell Sci. 2020 Jan 02. pii: jcs231811. [Epub ahead of print]133(1):
    Ayyub SA, Gao F, Lightowlers RN, Chrzanowska-Lightowlers ZM.
      In the canonical process of translation, newly completed proteins escape from the ribosome following cleavage of the ester bond that anchors the polypeptide to the P-site tRNA, after which the ribosome can be recycled to initiate a new round of translation. Not all protein synthesis runs to completion as various factors can impede the progression of ribosomes. Rescuing of stalled ribosomes in mammalian mitochondria, however, does not share the same mechanisms that many bacteria use. The classic method for rescuing bacterial ribosomes is trans-translation. The key components of this system are absent from mammalian mitochondria; however, four members of a translation termination factor family are present, with some evidence of homology to members of a bacterial back-up rescue system. To date, there is no definitive demonstration of any other member of this family functioning in mitoribosome rescue. Here, we provide an overview of the processes and key players of canonical translation termination in both bacteria and mammalian mitochondria, followed by a perspective of the bacterial systems used to rescue stalled ribosomes. We highlight any similarities or differences with the mitochondrial translation release factors, and suggest potential roles for these proteins in ribosome rescue in mammalian mitochondria.
    Keywords:  ArfA; ArfB; ArfT; C12orf65; ICT1; Mammalian mitochondria; Mitoribosomes; MtRF1; Release factor; Stalled ribosome; Trans-translation; Translation termination
    DOI:  https://doi.org/10.1242/jcs.231811
  3. Am J Hum Genet. 2019 Dec 23. pii: S0002-9297(19)30469-0. [Epub ahead of print]
    Gusic M, Schottmann G, Feichtinger RG, Du C, Scholz C, Wagner M, Mayr JA, Lee CY, Yépez VA, Lorenz N, Morales-Gonzalez S, Panneman DM, Rötig A, Rodenburg RJT, Wortmann SB, Prokisch H, Schuelke M.
      Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.
    Keywords:  Q-cycle; Rieske iron-sulfur protein; alopecia; cardiomyopathy; microscale respiratory; mitochondrial complex III deficiency; mitochondrial import sequence; mitochondriopathy; mutation
    DOI:  https://doi.org/10.1016/j.ajhg.2019.12.005
  4. J Clin Invest. 2020 Jan 02. pii: 129202. [Epub ahead of print]130(1): 20-28
    Khan S, Ince-Dunn G, Suomalainen A, Elo LL.
      High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.
    DOI:  https://doi.org/10.1172/JCI129202