bims-cytox1 2018-12-30 papers

bims-cytox1

Biomed News

on Cytochrome oxidase subunit 1

Issue of 2018–12–30
nine papers selected by
Gavin McStay, Staffordshire University

Mitochondrial DNA variations in tongue squamous cell carcinoma.
Sideroblastic anemia associated with multisystem mitochondrial disorders.
The mitochondrial transfer RNAAsp A7551G mutation may contribute to the clinical expression of deafness associated with the A1555G mutation in a pedigree with hearing impairment.
Assessing the fitness consequences of mitonuclear interactions in natural populations.
A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity.
Whole-exome sequencing reveals a novel mutation of MT-ND5 gene in a mitochondrial cardiomyopathy pedigree: Patients who show biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance.
Subunit Asa3 ensures the attachment of the peripheral stalk to the membrane sector of the dimeric ATP synthase of Polytomella sp.
NDUFAF5 variants manifest phenotypically heterogeneously.
Heteroplasmic Mutations and Polymorphisms in the Cyb Gene of Mitochondrial DNA in Canine Mast Cell Tumours.

Biomed Rep. 2019 Jan;10(1): 23-28

Mitochondrial DNA variations in tongue squamous cell carcinoma.

Hong-Ying Shu, Hong-Chao Li, Wan-Qin Xie, Bin Ni, Hai-Yan Zhou.

  Tongue squamous cell carcinoma (TSCC) is the most common type of oral carcinoma. Mitochondrial DNA (mtDNA) is a circular DNA molecule of 16,569 bp, which functionally encompasses a regulatory non-coding region (D-loop) and 37 encoding genes that correspond to 13 subunits of respiratory chain complexes (I, III, IV and V), 22 transfer RNAs and 2 ribosomal (r)RNAs. Recently, mtDNA has been implicated as a mutation hotspot in various tumors. However, to our knowledge mtDNA alteration in TSCC has not been investigated to date. In the present study, the mitochondrial genomes of tongue carcinoma, adjacent non-cancerous tissue and peripheral blood samples from 8 patients with TSCC were sequenced and aligned with the revised Cambridge Reference Sequence. Overall, only one synonymous mutation, which mapped to the NADH:ubiquinone oxidoreductase core subunit 5 gene, was observed in the tongue carcinoma sample from a single patient. A further 21 polymorphisms were identified, including six in the non-coding region (D-loop), five in Complex I, three in Complex III, two in Complex IV, two in Complex V and three in rRNA. In addition, mitochondrial microsatellite instability (mtMSI) was detected in 2/8 tongue carcinoma samples, and localized in the D310 region. These variations, particularly the polymorphisms and mtMSI, imply that the mitochondrial genome may be a hotspot of genome alteration in tongue cancer. Further investigation is expected to reveal the role of mtDNA alteration in TSCC development, as well as its clinical implications.

Keywords:  mitochondrial DNA; mitochondrial microsatellite instability; mutation; polymorphism; tongue carcinoma

DOI:  https://doi.org/10.3892/br.2018.1167
Pediatr Blood Cancer. 2018 Dec 26. e27591

Sideroblastic anemia associated with multisystem mitochondrial disorders.

Marketa Tesarova, Alzbeta Vondrackova, Hana Stufkova, Lenka Veprekova, Viktor Stranecky, Kamila Berankova, Hana Hansikova, Martin Magner, Natalia Galoova, Tomas Honzik, Elena Vodickova, Jan Stary, Jiri Zeman.

   BACKGROUND: Sideroblastic anemia represents a heterogeneous group of inherited or acquired diseases with disrupted erythroblast iron utilization, ineffective erythropoiesis, and variable systemic iron overload. In a cohort of 421 patients with multisystem mitochondrial diseases, refractory anemia was found in 8 children.
RESULTS: Five children had sideroblastic anemia with increased numbers of ring sideroblasts >15%. Two of the children had a fatal course of MLASA1 syndrome (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia [SA]) due to a homozygous, 6-kb deletion in the PUS1 gene, part of the six-member family of pseudouridine synthases (pseudouridylases). Large homozygous deletions represent a novel cause of presumed PUS1-loss-of-function phenotype. The other three children with SA had Pearson syndrome (PS) due to mtDNA deletions of 4 to 8 kb; two of these children showed early onset of PS and died due to repeated sepsis; the other child had later onset of PS and survived as the hematological parameters normalized and the disease transitioned to Kearns-Sayre syndrome. In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor.
CONCLUSIONS: Sideroblastic anemia was found in fewer than 1.2% of patients with multisystem mitochondrial disease, and it was usually associated with an unfavorable prognosis.

Keywords:  MLASA; Pearson syndrome; mitochondrial disorders; mtDNA; ring sideroblasts; sideroblastic anemia

DOI:  https://doi.org/10.1002/pbc.27591
Mol Med Rep. 2018 Dec 24.

The mitochondrial transfer RNAAsp A7551G mutation may contribute to the clinical expression of deafness associated with the A1555G mutation in a pedigree with hearing impairment.

Jing Zhang, Bo Lu, Wei-Wei Xia, Bin Fang, Xiao-Xia Ding, Guang-Wei Hu.

The role of mitochondrial (mt)DNA variations in hearing loss have been studied extensively; in particular, the well‑known pathogenic A1555G mutation in the human mitochondrial 12S ribosomal RNA gene is associated with aminoglycoside‑induced and non‑syndromic hearing loss. The present paper described a Chinese pedigree with hearing impairments. We first performed polymerase chain reaction and direct sequence analysis for the mtDNA genes. Additionally, the GJB2 gene mutations were also genotyped. Notably, this family had a very high penetrance of deafness (66.7 and 33.3%; including and excluding aminoglycoside use, respectively). Sequence analysis of the mtDNA genes from the matrilineal relatives identified the occurrence of A1555G mutation, as well as the tRNAAsp A7551G mutation. The A7551G mutation occurred at position 37 in the anticodon stem of tRNAAsp, which is extremely conserved among various species. The nucleotide at this position is often chemically modified and thus contributes to the maintenance of functional tRNAAsp, therefore, this mutation may cause an imbalance in the level of tRNAAsp and lead to mitochondrial dysfunction which is involved in the pathogenesis of hearing loss. Taken together, the findings of the present study demonstrated that the A7551G mutation may have contributed to the deafness phenotype caused by the A1555G mutation.

DOI: https://doi.org/10.3892/mmr.2018.9790
Biol Rev Camb Philos Soc. 2018 Dec 26.

Assessing the fitness consequences of mitonuclear interactions in natural populations.

Geoffrey E Hill, Justin C Havird, Daniel B Sloan, Ronald S Burton, Chris Greening, Damian K Dowling.

  Metazoans exist only with a continuous and rich supply of chemical energy from oxidative phosphorylation in mitochondria. The oxidative phosphorylation machinery that mediates energy conservation is encoded by both mitochondrial and nuclear genes, and hence the products of these two genomes must interact closely to achieve coordinated function of core respiratory processes. It follows that selection for efficient respiration will lead to selection for compatible combinations of mitochondrial and nuclear genotypes, and this should facilitate coadaptation between mitochondrial and nuclear genomes (mitonuclear coadaptation). Herein, we outline the modes by which mitochondrial and nuclear genomes may coevolve within natural populations, and we discuss the implications of mitonuclear coadaptation for diverse fields of study in the biological sciences. We identify five themes in the study of mitonuclear interactions that provide a roadmap for both ecological and biomedical studies seeking to measure the contribution of intergenomic coadaptation to the evolution of natural populations. We also explore the wider implications of the fitness consequences of mitonuclear interactions, focusing on central debates within the fields of ecology and biomedicine.

Keywords:  coadaptation; coevolution; epistatic interactions; fitness; gene flow; mitochondria; mitochondrial medicine; speciation

DOI:  https://doi.org/10.1111/brv.12493
EMBO J. 2018 Dec 27. pii: e98786. [Epub ahead of print]

A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity.

Yanjun Li, Yanhong Xue, Xiaojun Xu, Guopeng Wang, Yiqun Liu, Hao Wu, Wenhui Li, Yueying Wang, Ziheng Chen, Weilin Zhang, Yushan Zhu, Wei Ji, Tao Xu, Lei Liu, Quan Chen.

  Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age-related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non-aggresomal mitochondrion-associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1-dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.

Keywords:  cellular senescence; mitochondria; mitochondrial quality control; mitophagy; proteostatic stress

DOI:  https://doi.org/10.15252/embj.201798786
Anatol J Cardiol. 2019 Jan;21(1): 18-24

Whole-exome sequencing reveals a novel mutation of MT-ND5 gene in a mitochondrial cardiomyopathy pedigree: Patients who show biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance.

Nianwei Zhou, Lu Tang, Yingying Jiang, Shengmei Qin, Jie Cui, Yanan Wang, Wenqing Zhu, Weipeng Zhao, Cuizhen Pan, Xianhong Shu.

OBJECTIVE: The aim of the present study was to determine whether pathogenic mutations were present in families with mitochondrial cardiomyopathy that presented during adolescence.
METHODS: The proband was a 21-year-old man who presented clinically with palpitations, chest tightness, pulmonary hypertension, and limited exercise tolerance. Cardiac magnetic resonance imaging studies showed biventricular cardiac hypertrophy. We determine whether pathogenic mutations were present by whole-exome sequencing (WES) in families.
RESULTS: Screening of the family using tandem mass spectrometry showed elevated lactic acid levels, glutaric aciduria, a mildly increased glutarylcarnitine-to-octanoylcarnitine ratio, and normal blood α-glucosidase, which was consistent with a respiratory chain complex 1 metabolic disorder. We identified a novel mutation of MT-ND5, c.1315A>G (p.Thr439Ala). Skeletal muscle biopsy histology showed predominantly ragged red fibers and few ragged blue fibers, which was consistent with mitochondrial myopathy.
CONCLUSION: In the present study, we identified a novel mutation of MT-ND5, c.1315A>G (p.Thr439Ala), in a family pedigree using WES.

DOI: https://doi.org/10.14744/AnatolJCardiol.2018.53258
Biochem Biophys Res Commun. 2018 Dec 22. pii: S0006-291X(18)32807-9. [Epub ahead of print]

Subunit Asa3 ensures the attachment of the peripheral stalk to the membrane sector of the dimeric ATP synthase of Polytomella sp.

Lilia Colina-Tenorio, Héctor Miranda-Astudillo, Alain Dautant, Miriam Vázquez-Acevedo, Marie-France Giraud, Diego González-Halphen.

  The mitochondrial ATP synthase of Polytomella exhibits a peripheral stalk and a dimerization domain built by the Asa subunits, unique to chlorophycean algae. The topology of these subunits has been extensively studied. Here we explored the interactions of subunit Asa3 using Far Western blotting and subcomplex reconstitution, and found it associates with Asa1 and Asa8. We also identified the novel interactions Asa1-Asa2 and Asa1-Asa7. In silico analyses of Asa3 revealed that it adopts a HEAT repeat-like structure that points to its location within the enzyme based on the available 3D-map of the algal ATP synthase. We suggest that subunit Asa3 is instrumental in securing the attachment of the peripheral stalk to the membrane sector, thus stabilizing the dimeric mitochondrial ATP synthase.

Keywords:  ATP synthase; Asa subunit; HEAT repeats; Peripheral stalk; Polytomella

DOI:  https://doi.org/10.1016/j.bbrc.2018.12.142
Mol Genet Metab Rep. 2019 Mar;18 8-9

NDUFAF5 variants manifest phenotypically heterogeneously.

Josef Finsterer.



Keywords:  Leigh syndrome; Mitochondrial; Multisystem disease; Respiratory chain; Stroke-like episode

DOI:  https://doi.org/10.1016/j.ymgmr.2018.11.005
In Vivo. 2019 Jan-Feb;33(1):33(1): 57-63

Heteroplasmic Mutations and Polymorphisms in the Cyb Gene of Mitochondrial DNA in Canine Mast Cell Tumours.

Anna Śmiech, Brygida Ślaska, Adam Bownik, Ludmiła Grzybowska-Szatkowska, Jarosław Dudka, Wojciech Łopuszyński.

   AIM: Identification of mutations and polymorphisms in the cytochrome b gene (Cyb) of mitochondrial DNA (mtDNA) in canine mast cell tumours and determinatiion of their association with the process of neoplastic transformation.
MATERIALS AND METHODS: The samples comprised tumour tissues and blood obtained from 34 dogs of various breeds. Mutations and polymorphisms in the Cyb gene were detected using amplification and sequencing methods.
RESULTS: Heteroplasmic mutations were detected at seven positions of mtDNA in 86% of the individuals. Blood and tumour heteroplasmy were recorded at five nucleotide positions of the Cyb gene, whereas tumour heteroplasmy was detected at two positions. Polymorphisms were detected at 14 Cyb gene positions in in the blood of 91% of dogs with mast cell tumours.
CONCLUSION: The presence of numerous mutations and polymorphisms of Cyb in the blood and tumour tissues and the high frequency of heteroplasmy indicate their involvement in the process of neoplastic transformation in dogs.

Keywords:  Cyb gene; dog; mast cell tumours; mitochondrial DNA; mtDNA; mutations

DOI:  https://doi.org/10.21873/invivo.11439