bims-cytox1 Biomed news on
Cytochrome oxidase subunit 1
Issue of 2018‒01‒21
four papers selected by
Gavin McStay
New York Institute of Technology


  1. Mol Genet Metab. 2018 Jan;doi: 10.1016/j.ymgme.2017.11.003123(1):
    Abstract:  BACKGROUND: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10). MATERIAL AND METHODS: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail. RESULTS: For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients. CONCLUSION: MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.
    Keywords:  Cardiomyopathy; Ketogenic diet; Lactic acidosis; Mitochondrial disease; Mitochondrial translation optimization 1; Oxidative Phosphorylation Defect
  2. Environ Mol Mutagen. 2018 Jan 14. doi: 10.1002/em.22169
    Abstract:  The inheritance of mitochondrial DNA (mtDNA) from mother to child is complicated by differences in the stability of the mitochondrial genome. Although the germ line mtDNA is protected through the minimization of replication between generations, sequence variation can occur either through mutation or due to changes in the ratio between distinct genomes that are present in the mother (known as heteroplasmy). Thus, the unpredictability in transgenerational inheritance of mtDNA may cause the emergence of pathogenic mitochondrial and cellular phenotypes in offspring. Studies of the role of mitochondrial metabolism in cancer have a long and rich history, but recent evidence strongly suggests that changes in mitochondrial genotype and phenotype play a significant role in the initiation, progression and treatment of cancer. At the intersection of these two fields lies the potential for emerging mtDNA mutations to drive carcinogenesis in the offspring. In this review, we suggest that this facet of transgenerational carcinogenesis remains underexplored and is a potentially important contributor to cancer. Environ. Mol. Mutagen., 2018. © 2018 Wiley Periodicals, Inc.
    Keywords:  cancer; heteroplasmy; mitochondrion; mutagenesis; transplacental
  3. Curr Med Chem. 2018 Jan 10. doi: 10.2174/0929867325666180111094336
    Abstract:  The diagnosis of mitochondrial diseases is still challenging due to clinical and genetical heterogeneity. The development of advanced technologies including Whole-Exome-Sequencing (WES) and Whole-Genome-Sequencing (WGS) have led to improvements in genetic diagnosis. However, a reliable biomarker in serum could enhance and ease the diagnosis and indeed reduce the need for muscle biopsy. Several studies suggest Fibroblast growth factor 21 (FGF-21) as a biomarker for diagnosis in mitochondrial disorders. It is known, that in patients with mitochondrial disorders, the expression of FGF-21 gets elevated in an effort to counteract the underlying metabolic deficiency. The growth and differentiation factor 15 (GDF-15) has been described as a potential biomarker for mitochondrial diseases, too. In the present review, a literature research, using PubMed database about the reliability of FGF-21 as a biomarker for mitochondrial disorders and its comparison with GDF-15 has been performed.
    Keywords:  COX; FGF-21; GDF-15; Mitochondrial diseases; biomarker; diagnosis.
  4. Int J Med Sci. 2018 ;doi: 10.7150/ijms.2107515(1):
    Abstract:  Objectives: Klinefelter syndrome (KS) is one of the most common sex-chromosome disorders as it affects up to 1 in every 600-1000 newborn males. Men with KS carry one extra X chromosome and they usually present a 47,XXY karyotype, but less frequent variants have also been reported in literature. KS typical symptoms include tall stature, gynecomastia, broad hips, hypogonadism and absent spermatogenesis. The syndrome is also related to a wide range of cognitive deficits, among which language-based learning disabilities and verbal cognition impairment are frequently diagnosed. The present study was carried out to investigate the role of mitochondrial subunits in KS, since the molecular mechanisms underlying KS pathogenesis are not fully understood. Methods: The study was performed by the next generation sequencing analysis and qRT-PCR assay. Results: We were able to identify a significant down-expression of mitochondrial encoded NADH: ubiquinone oxidoreductase core subunit 6 (MT-ND6) in men with KS. Conclusion: It is known that defects of the mtDNA encoding mitochondrial subunits are responsible for the malfunction of Complex I, which will eventually lead to the Complex I deficiency, the most common respiratory chain defect in human disorders. Since it has been shown that decreased Complex I protein levels could induce apoptosis, wehypothesizethat the above-mentioned MT-ND6 down-expression contributes to the wide range of phenotypes observed in men with KS.
    Keywords:  Klinefelter syndrome; MT-ND6; NGS analysis; cognitive deficits; qRT-PCR.