bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2019‒08‒25
three papers selected by
Gavin McStay
Staffordshire University


  1. Hum Mol Genet. 2019 Aug 22. pii: ddz202. [Epub ahead of print]
    Oláhová M, Berti CC, Collier JJ, Alston CL, Jameson E, Jones SA, Edwards N, He L, Chinnery PF, Horvath R, Goffrini P, Taylor RW, Sayer JA.
      BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants, include Growth Retardation, Aminoaciduria, Chloestasis, Iron overload, Lactic acidosis and Early death (GRACILE syndrome) and Björnstad syndrome, characterised by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C>T, p.(Arg56*) together with a novel heterozygous variant c.205C>T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C>T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second was an infant who presented with a classical GRACILE syndrome leading to death at 4 months of age. A decrease in BCS1L protein levels was seen in both patients and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient's muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C>T, p.(Arg69Cys) and c.325C>T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.
    DOI:  https://doi.org/10.1093/hmg/ddz202
  2. Cell Biol Int. 2019 Aug 23.
    Huddleston ME, Xiao N, Both AP, Gordon DM.
      Key to mitochondrial activities is the maintenance of mitochondrial morphology, specifically cristae structures formed by the invagination of the inner membrane that are enriched in proteins of the electron transport chain. In S. cerevisiae, these cristae folds are a result of the membrane fusion activities of Mgm1p and the membrane bending properties of ATP synthase oligomerization. An additional protein linked to mitochondrial morphology is Pcp1p, a serine protease responsible for the proteolytic processing of Mgm1p. Here we have used hydroxylamine-based random mutagenesis to identify amino acids important for Pcp1p peptidase activity. Using this approach we have isolated five single amino acid mutants that exhibit respiratory growth defects that correlate with loss of mitochondrial genome stability. Reduced Pcp1p protease activity was confirmed by immunoblotting with the accumulation of improperly processed Mgm1p. Ultra-structural analysis of mitochondrial morphology in these mutants found a varying degree of defects in cristae organization. However, not all of the mutants presented with decreased ATP synthase complex assembly as determined by BN-PAGE. Together, these data suggest that there is a threshold level of processed Mgm1p required to maintain ATP synthase super complex assembly and mitochondrial cristae organization. This article is protected by copyright. All rights reserved.
    Keywords:  ATP synthase; Blue Native-PAGE; Cristae structure; Mitochondrial morphology; Pcp1p; Peptidase activity
    DOI:  https://doi.org/10.1002/cbin.11219
  3. J Clin Med. 2019 Aug 20. pii: E1262. [Epub ahead of print]8(8):
    Barbosa-Gouveia S, González-Vioque E, Borges F, Gutiérrez-Solana L, Wintjes L, Kappen A, van den Heuvel L, Leis R, Rodenburg R, Couce ML.
      Complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase) is the largest complex of the mitochondrial oxidative phosphorylation system (OXPHOS) system. Forty-four subunits encoded in nuclear and mitochondrial genomes compose this multiprotein complex, its assembly being a highly complex process involving at least 15 additional nuclear encoded assembly factors. Complex I deficiency is a mitochondrial disorder usually associated with early-onset severe multisystem disorders characterized by highly variable clinical manifestations. Flavin adenine dinucleotide (FAD)-dependent oxidoreductase domain-containing protein 1 (FOXRED1) is a complex I assembly factor. To date, only five patients with mitochondrial complex I deficiency due to mutations in FOXRED1 have been characterized. Here, we describe a child with ataxia, epilepsy and psychomotor developmental delay carrying two heterozygous FOXRED1 variants, c.920G>A (p.Gly307Glu) and c.733+1G>A. We demonstrate the molecular mechanism supporting the pathogenicity of the FOXRED1 variants, showing a clear deficiency of complex I activity. The reduction in the steady-state level of complex I holoenzyme in patient fibroblasts, confirmed the pathogenicity of the variants and showed the molecular mechanism behind their pathogenicity. A comparison of the clinical presentation of the index case with the previously described cases allowed deepening our knowledge about the clinical variability associated with FOXRED1 defects.
    Keywords:  FOXRED1; complex I deficiency; epilepsy; mitochondrial disorders
    DOI:  https://doi.org/10.3390/jcm8081262