bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒04‒26
five papers selected by
Gavin McStay
Staffordshire University


  1. Mol Cell Proteomics. 2020 Apr 21. pii: mcp.RA120.002076. [Epub ahead of print]
    Hock DH, Reljic B, Ang CS, Muellner-Wong L, Mountford HS, Compton AG, Ryan MT, Thorburn DR, Stroud DA.
      Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist in the membrane insertion of subunits, attachment of co-factors, and stabilization of assembly intermediates. The major fraction of complexes I, III and IV are present together in large molecular structures known as respiratory chain supercomplexes. A number of assembly factors have been proposed as required for supercomplex assembly, including the hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines and extensive steady state, translation and affinity enrichment proteomics techniques we show that loss of HIGD2A leads to defects in the de novo biogenesis of mtDNA-encoded COX3, subsequent accumulation of complex IV intermediates and turnover of COX3 partner proteins. Deletion of HIGD2A also leads to defective complex IV activity. The impact of HIGD2A loss on complex IV was not altered by growth under hypoxic conditions, consistent with its role being in basal complex IV assembly. While in the absence of HIGD2A we show that mitochondria do contain an altered supercomplex assembly, we demonstrate it to harbor a crippled complex IV lacking COX3. Our results redefine HIGD2A as a classical assembly factor required for building the COX3 module of complex IV.
    Keywords:  Cytochrome c oxidase; Energy metabolism; Knockouts*; Mitochondria function or biology; Mitochondrial disease; OXPHOS; Translation*; mitochondria; mtDNA translation; respirasome
    DOI:  https://doi.org/10.1074/mcp.RA120.002076
  2. Neuromuscul Disord. 2020 Mar 05. pii: S0960-8966(20)30061-4. [Epub ahead of print]
    Joshi PR, Baty K, Hopton S, Cordts I, Falkous G, Schoser B, Blakely EL, Taylor RW, Deschauer M.
      Progressive external ophthalmoplegia is typically associated with single or multiple mtDNA deletions but occasionally mtDNA single nucleotide variants within mitochondrial transfer RNAs (mt-tRNAs) are identified. We report a 34-year-old female sporadic patient with progressive external ophthalmoplegia accompanied by exercise intolerance but neither fixed weakness nor multisystemic involvement. Histopathologically, abundant COX-deficient fibres were present in muscle with immunofluorescence analysis confirming the loss of mitochondrial complex I and IV proteins. Molecular genetic analysis identified a rare heteroplasmic m.15990C>T mt-tRNAPro variant reported previously in a single patient with childhood-onset myopathy. The variant in our patient was restricted to muscle. Single muscle fibre analysis identified higher heteroplasmy load in COX-deficient fibres than COX-normal fibres, confirming segregation of high heteroplasmic load with a biochemical defect. Our case highlights the phenotypic variability typically observed with pathogenic mt-tRNA mutations, whilst the identification of a second case with the m.15990C>T mutation not only confirms pathogenicity but shows that de novo mt-tRNA point mutations can arise in multiple, unrelated patients.
    Keywords:  Mitochondria; Pathogenicity; Progressive external ophthalmoplegia; de novo mutation; tRNA Pro
    DOI:  https://doi.org/10.1016/j.nmd.2020.02.020
  3. Cell Rep. 2020 Apr 21. pii: S2211-1247(20)30441-1. [Epub ahead of print]31(3): 107541
    Formosa LE, Muellner-Wong L, Reljic B, Sharpe AJ, Jackson TD, Beilharz TH, Stojanovski D, Lazarou M, Stroud DA, Ryan MT.
      Mitochondrial complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly and integration of distinct intermediate modules, mediated by numerous assembly factors. The mitochondrial complex I intermediate assembly (MCIA) complex, containing assembly factors NDUFAF1, ECSIT, ACAD9, and TMEM126B, is required for building the intermediate ND2-module. The role of the MCIA complex and the involvement of other proteins in the biogenesis of this module is unclear. Cell knockout studies reveal that while each MCIA component is critical for complex I assembly, a hierarchy of stability exists centered on ACAD9. We also identify TMEM186 and COA1 as bona fide components of the MCIA complex with loss of either resulting in MCIA complex defects and reduced complex I assembly. TMEM186 enriches with newly translated ND3, and COA1 enriches with ND2. Our findings provide new functional insights into the essential nature of the MCIA complex in complex I assembly.
    Keywords:  MCIA complex; NADH-ubiquinone dehydrogenase; assembly factors; complex I; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2020.107541
  4. Mitochondrion. 2020 Apr 15. pii: S1567-7249(19)30348-4. [Epub ahead of print]
    Mukherjee S, Ghosh A.
      The mitochondrial respiratory chain (MRC) is comprised of ∼92 nuclear and mitochondrial DNA-encoded protein subunits that are organized into five different multi-subunit respiratory complexes. These complexes produce 90% of the ATP required for cell sustenance. Specific sets of subunits are assembled in a modular or non-modular fashion to construct the MRC complexes. The complete assembly process is gradually chaperoned by a myriad of assembly factors that must coordinate with several other prosthetic groups to reach maturity, makingthe entire processextensively complicated. Further, the individual respiratory complexes can be integrated intovarious giant super-complexes whose functional roles have yet to be explored. Mutations in the MRC subunits and in the related assembly factors often give rise to defects in the proper assembly of the respiratory chain, which then manifests as a group of disorders called mitochondrial diseases, the most common inborn errors of metabolism. This review summarizes the current understanding of the biogenesis of individual MRC complexes and super-complexes, and explores how mutations in the different subunits and assembly factors contribute to mitochondrial disease pathology.
    Keywords:  Assembly factors; Mitochondrial diseases; Mitochondrial respiratory chain; Mutations; Super-complexes
    DOI:  https://doi.org/10.1016/j.mito.2020.04.002
  5. Biochem Soc Trans. 2020 Apr 20. pii: BST20190930. [Epub ahead of print]
    Caruana NJ, Stroud DA.
      The four complexes of the mitochondrial respiratory chain are critical for ATP production in most eukaryotic cells. Structural characterisation of these complexes has been critical for understanding the mechanisms underpinning their function. The three proton-pumping complexes, Complexes I, III and IV associate to form stable supercomplexes or respirasomes, the most abundant form containing 80 subunits in mammals. Multiple functions have been proposed for the supercomplexes, including enhancing the diffusion of electron carriers, providing stability for the complexes and protection against reactive oxygen species. Although high-resolution structures for Complexes III and IV were determined by X-ray crystallography in the 1990s, the size of Complex I and the supercomplexes necessitated advances in sample preparation and the development of cryo-electron microscopy techniques. We now enjoy structures for these beautiful complexes isolated from multiple organisms and in multiple states and together they provide important insights into respiratory chain function and the role of the supercomplex. While we as non-structural biologists use these structures for interpreting our own functional data, we need to remind ourselves that they stand on the shoulders of a large body of previous structural studies, many of which are still appropriate for use in understanding our results. In this mini-review, we discuss the history of respiratory chain structural biology studies leading to the structures of the mammalian supercomplexes and beyond.
    Keywords:  mitochondria; oxidative phosphorylation; structural biology
    DOI:  https://doi.org/10.1042/BST20190930