bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2018‒12‒02
eight papers selected by
Gavin McStay
Staffordshire University


  1. Mol Genet Metab. 2018 Nov 08. pii: S1096-7192(18)30596-1. [Epub ahead of print]
    Simon MT, Eftekharian SS, Stover AE, Osborne AF, Braffman BH, Chang RC, Wang RY, Steenari MR, Tang S, Hwu PW, Taft RJ, Benke PJ, Abdenur JE.
      Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.
    Keywords:  Complex I; Hyponatremia; Leigh syndrome; Mitochondrial disease; NDUFAF5; Splicing
    DOI:  https://doi.org/10.1016/j.ymgme.2018.11.001
  2. DNA Cell Biol. 2018 Nov 27.
    Heinemeyer T, Stemmet M, Bardien S, Neethling A.
      Mitochondria are critical for cellular survival, and for their proper functioning, translocation of ∼1500 proteins across the mitochondrial membranes is required. The translocase of the outer (TOMM) and inner mitochondrial membrane (TIMM) complexes are major components of this translocation machinery. Through specific processes, preproteins and other molecules are imported, translocated, and directed to specific mitochondrial compartments for their function. In this study, we review the association of subunits of these complexes with human disease. Pathogenic mutations have been identified in the TIMM8A (DDP) and DNAJC19 (TIMM14) genes and are linked to Mohr-Tranebjærg syndrome and dilated cardiomyopathy syndrome (with and without ataxia), respectively. Polymorphisms in TOMM40 have been associated with Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease with dementia, dementia with Lewy bodies, nonpathological cognitive aging, and various cardiovascular-related traits. Furthermore, reduced protein expression levels of several complex subunits have been associated with Parkinson's disease, Meniere's disease, and cardiovascular disorders. However, increased mRNA and protein levels of complex subunits are found in cancers. This review highlights the importance of the mitochondrial import machinery in human disease and stresses the need for further studies. Ultimately, this knowledge may prove to be critical for the development of therapeutic modalities for these conditions.
    Keywords:  TIMM; TOMM; disease; gene and protein expression; genetics; mitochondrial protein import
    DOI:  https://doi.org/10.1089/dna.2018.4292
  3. Genetics. 2018 Nov 29. pii: genetics.301546.2018. [Epub ahead of print]
    Vijayraghavan S, Kozmin SG, Strope PK, Skelly DA, Lin Z, Kennell J, Magwene PM, Dietrich FS, McCusker JH.
      Mitochondrial genome variation and its effects on phenotypes have been widely analyzed in higher eukaryotes but less so in the model eukaryote Saccharomyces cerevisiae Here, we describe mitochondrial genome variation in 96 diverse S. cerevisiae strains and assess associations between mitochondrial genotype and phenotypes as well as nuclear-mitochondrial epistasis. We associate sensitivity to the ATP synthase inhibitor oligomycin with SNPs in the mitochondrially-encoded ATP6gene. We describe the use of iso-nuclear F1 pairs, the mitochondrial genome equivalent of reciprocal hemizygosity analysis, to identify and analyze mitochondrial genotype-dependent phenotypes. Using iso-nuclear F1 pairs, we analyze the oligomycin phenotype-ATP6 association and find extensive nuclear-mitochondrial epistasis. Similarly, in iso-nuclear F1 pairs, we identify many additional mitochondrial genotype-dependent respiration phenotypes, for which there was no association in the 96 strains, and again find extensive nuclear-mitochondrial epistasis that likely contributes to the lack of association in the 96 strains. Finally, in iso-nuclear F1 pairs, we identify novel mitochondrial genotype-dependent non-respiration phenotypes - resistance to cycloheximide, ketoconazole, and copper. We discuss potential mechanisms and the implications of mitochondrial genotype and of nuclear-mitochondrial epistasis effects on respiratory and non-respiratory quantitative traits.
    Keywords:  Saccharomyces cerevisiae; introgression; mitochondrial genome variation; nuclear-mitochondrial epistasis; phenotypic variation; transgression
    DOI:  https://doi.org/10.1534/genetics.118.301546
  4. Kidney Int. 2018 Nov 21. pii: S0085-2538(18)30645-8. [Epub ahead of print]
    Johnson SC, Martinez F, Bitto A, Gonzalez B, Tazaerslan C, Cohen C, Delaval L, Timsit J, Knebelmann B, Terzi F, Mahal T, Zhu Y, Morgan PG, Sedensky MM, Kaeberlein M, Legendre C, Suh Y, Canaud G.
      Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.
    Keywords:  chronic kidney disease; mitochondria
    DOI:  https://doi.org/10.1016/j.kint.2018.08.038
  5. Mitochondrion. 2018 Nov;pii: S1567-7249(18)30050-3. [Epub ahead of print]43 43-52
    Daniil Z, Kotsiou OS, Grammatikopoulos A, Peletidou S, Gkika H, Malli F, Antoniou K, Vasarmidi E, Mamuris Z, Gourgoulianis K, Zifa E.
      Mitochondrial reactive oxygen species production may lead to tissue injury associated with two respiratory disorders of unknown origin which are shared by common tissue fibrosis, IPF and sarcoidosis. Sequence analysis of 22 mt-tRNA genes and parts of their flanking genes revealed 32 and 45 mutations in 38/40 IPF and 69/85 sarcoidosis patients respectively. 4 novel mutations were identified. 15/32 and 25/45 mutations were exclusively expressed while 12/32 and 17/45 mutations predominantly occurred in IPF and sarcoidosis group respectively, compared to healthy controls. Novel mutation combinations were solely expressed in disease. Hence, a mitochondrial-mediated pathogenic pathway seems to underlie both entities.
    Keywords:  Interstitial pulmonary fibrosis; Mitochondrial transfer RNA; Mutation; Sarcoidosis; Variants
    DOI:  https://doi.org/10.1016/j.mito.2018.10.004
  6. Int J Cardiol. 2018 Oct 23. pii: S0167-5273(18)34949-0. [Epub ahead of print]
    Brambilla A, Favilli S, Olivotto I, Calabri GB, Porcedda G, De Simone L, Procopio E, Pasquini E, Donati MA.
      BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like (MELAS) syndrome is a rare condition with heterogeneous clinical presentation. Cardiac involvement commonly develops during adulthood, comprising both structural and conduction/arrhythmic abnormalities; early paediatric onset has rarely been reported. We describe the clinical profile, outcome and clinical implication of MELAS-associated cardiomyopathy at a tertiary referral centre.METHODS: From 2000 to 2016 we enrolled 21 patients affected by genetically-proven MELAS. Patients were followed-up at least annually over a mean of 8.5 years.
    RESULTS: All patients carried the MT-TL1 3243A>G mutation. Cardiac involvement was documented in 8 (38%) patients (three <18 years; five ≥18 years), including 6 (75%) with hypertrophic cardiomyopathy, 1 (12.5%) with dilated cardiomyopathy, and 1 (12.5%) with persistent pulmonary hypertension. During follow-up, 3 patients died, all with cardiac onset <18 years. The cause of death, however, was non-cardiac (infections, respiratory failure, stroke). Neither events nor cardiac progression were recorded among patients with onset ≥18 years. Adult cardiologists were responsible for 5/8 of referrals, even in patients with long-standing extra-cardiac involvement.
    CONCLUSIONS: Cardiac involvement was found in over 1/3 of patients with MELAS syndrome, and exhibited a bimodal age-related distribution with distinct final outcomes. Paediatric-onset cardiomyopathy represented a hallmark of systemic disease severity, without being the main determinant of outcome. Conversely, adult-onset cardiomyopathy appeared to represent a mild and non-progressive mid-term manifestation. Adult cardiologists played an important role in the diagnostic process, triggering suspicion of MELAS in most of patients diagnosis >18 years.
    Keywords:  MELAS syndrome; Metabolic cardiomyopathy; Mitochondria
    DOI:  https://doi.org/10.1016/j.ijcard.2018.10.051
  7. Plant Physiol. 2018 Nov 28. pii: pp.01286.2018. [Epub ahead of print]
    Kolli R, Soll J, Carrie C.
      The evolutionarily conserved YidC/Oxa1/Alb3 proteins are involved in the insertion of membrane proteins in all domains of life. In plant mitochondria, individual knockouts of OXA1a, OXA2a and OXA2b are embryo-lethal. In contrast to other members of the protein family, OXA2a and OXA2b contain a tetratricopeptide repeat (TPR) domain at the C-terminus. Here, the role of Arabidopsis thaliana OXA2b was determined by using viable mutant plants that were generated by complementing homozygous lethal OXA2b T-DNA insertional mutants with a C-terminally truncated OXA2b lacking the TPR domain. The truncated-OXA2b-complemented plants displayed severe growth retardation due to a strong reduction in the steady state abundance and enzyme activity of the mitochondrial respiratory chain complex IV. The TPR domain of OXA2b directly interacts with cytochrome c oxidase subunit 2 (COX2), aiding in efficient membrane insertion and translocation of its C-terminus. Thus, OXA2b is crucial for the biogenesis of complex IV in plant mitochondria.
    DOI:  https://doi.org/10.1104/pp.18.01286
  8. Proc Natl Acad Sci U S A. 2018 Nov 26. pii: 201810946. [Epub ahead of print]
    Luo S, Valencia CA, Zhang J, Lee NC, Slone J, Gui B, Wang X, Li Z, Dell S, Brown J, Chen SM, Chien YH, Hwu WL, Fan PC, Wong LJ, Atwal PS, Huang T.
      Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.
    Keywords:  biparental inheritance; human genetics; mitochondria; mtDNA; paternal transmission
    DOI:  https://doi.org/10.1073/pnas.1810946115