bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2022–02–06
eight papers selected by
Gavin McStay, Staffordshire University
  1. Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
  2. Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
  3. Understanding the nomenclature of mitochondrial DNA mutations through examples of two specific disease entities: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and Leber hereditary optic neuropathy.
  4. Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.
  5. Leigh syndrome: a study of 209 patients at the Beijing Children's Hospital.
  6. Identification of a novel homozygous SCO2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.
  7. Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
  8. Identification of polymorphisms in mitochondrial cytochrome c oxidase genes as risk factors for gastric cancer.
  1. Front Cell Dev Biol. 2021 ;9 796128
    Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
    Alfredo Cabrera-Orefice, Alisa Potter, Felix Evers, Johannes F Hevler, Sergio Guerrero-Castillo.
      Complexome profiling (CP) is a state-of-the-art approach that combines separation of native proteins by electrophoresis, size exclusion chromatography or density gradient centrifugation with tandem mass spectrometry identification and quantification. Resulting data are computationally clustered to visualize the inventory, abundance and arrangement of multiprotein complexes in a biological sample. Since its formal introduction a decade ago, this method has been mostly applied to explore not only the composition and abundance of mitochondrial oxidative phosphorylation (OXPHOS) complexes in several species but also to identify novel protein interactors involved in their assembly, maintenance and functions. Besides, complexome profiling has been utilized to study the dynamics of OXPHOS complexes, as well as the impact of an increasing number of mutations leading to mitochondrial disorders or rearrangements of the whole mitochondrial complexome. Here, we summarize the major findings obtained by this approach; emphasize its advantages and current limitations; discuss multiple examples on how this tool could be applied to further investigate pathophysiological mechanisms and comment on the latest advances and opportunity areas to keep developing this methodology.
    Keywords:  complexome profiling; disease; mass spectrometry; mitochondria; oxidative phosphorylation; protein complex; protein-protein interaction (PPI); proteomics
    DOI:  https://doi.org/10.3389/fcell.2021.796128
  2. Biol Chem. 2022 Jan 31.
    Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
    Nupur Sharma, Christof Osman.
      The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.
    Keywords:  MBA1; MDM38; OXA1; RRM; Walker motifs; mitoribosome
    DOI:  https://doi.org/10.1515/hsz-2021-0398
  3. J Am Assoc Nurse Pract. 2022 Feb 01. 34(2): 217-219
    Understanding the nomenclature of mitochondrial DNA mutations through examples of two specific disease entities: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and Leber hereditary optic neuropathy.
    Beth Heuer, Diane C Seibert.
       ABSTRACT: Mitochondrial diseases are genetic disorders that can arise either from maternally inherited mitochondrial DNA (mtDNA) or from mutations in nuclear DNA. This article is the second in a series of papers reviewing mitochondrial genetics and several of the disorders associated with mitochondrial gene variants. With a prevalence of 1:∼4,300 persons, mitochondrial disorders are diagnostic entities with which nurse practitioners should be familiar. In describing genetic mutations, numbering nucleotides (nuclear or mtDNA) is critical for communicating exactly where a variation has occurred in a stretch of nucleotides. This article discusses the nomenclature associated with mtDNA mutations, using the examples of mutations causing mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and Leber hereditary optic neuropathy. Pathophysiology, symptoms, and treatment options for these disease entities are discussed.
    DOI:  https://doi.org/10.1097/JXX.0000000000000693
  4. Genetics. 2022 Jan 20. pii: iyac007. [Epub ahead of print]
    Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.
    Anna M Kabala, Krishia Binko, François Godard, Camille Charles, Alain Dautant, Emilia Baranowska, Natalia Skoczen, Kewin Gombeau, Marine Bouhier, Hubert D Becker, Sharon H Ackerman, Lars M Steinmetz, Déborah Tribouillard-Tanvier, Rosa Kucharczyk, Jean-Paul di Rago.
      The yeast mitochondrial ATP synthase is an assembly of 28 subunits of 17 types of which 3 (subunits 6, 8, and 9) are encoded by mitochondrial genes while the 14 others have a nuclear genetic origin. Within the membrane domain (FO) of this enzyme, the subunit 6 and a ring of 10 identical subunits 9 transport protons across the mitochondrial inner membrane coupled to ATP synthesis in the extra-membrane structure (F1) of ATP synthase. As a result of their dual genetic origin, the ATP synthase subunits are synthesized in the cytosol and inside the mitochondrion. How they are produced in the proper stoichiometry from two different cellular compartments is still poorly understood. The experiments herein reported show that the rate of translation of the subunits 9 and 6 is enhanced in strains with mutations leading to specific defects in the assembly of these proteins. These translation modifications involve assembly intermediates interacting with subunits 6 and 9 within the final enzyme and cis-regulatory sequences that control gene expression in the organelle. In addition to enabling a balanced output of the ATP synthase subunits, these assembly-dependent feedback loops are presumably important to limit the accumulation of harmful assembly intermediates that have the potential to dissipate the mitochondrial membrane electrical potential and the main source of chemical energy of the cell.
    Keywords:  ATP synthase; Mitochondria; Mitochondria DNA; Mitochondrial biogenesis; Mitochondrial gene expression; yeast
    DOI:  https://doi.org/10.1093/genetics/iyac007
  5. Ann Neurol. 2022 Jan 30.
    Leigh syndrome: a study of 209 patients at the Beijing Children's Hospital.
    Sarah L Stenton, Ying Zou, Hua Cheng, Zhimei Liu, Junling Wang, Danmin Shen, Hong Jin, Changhong Ding, Xiaolu Tang, Suzhen Sun, Hong Han, Yanli Ma, Weihua Zhang, Ruifeng Jin, Hua Wang, Dan Sun, Jun Lan Lv, Holger Prokisch, Fang Fang.
       OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival.
    METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis.
    RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥ 90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176 T > C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993 T > C and m.9176 T > C), SURF1, and ALDH5A1 (≤50% 3 year survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year survival).
    INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counselling, and to the design and monitoring of future clinical trials, the next frontier of LS research. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ana.26313
  6. Hum Mutat. 2022 Feb 02.
    Identification of a novel homozygous SCO2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.
    Andrea Gangfuß, Andreas Hentschel, Nina Rademacher, Albert Sickmann, Burkhard Stüve, Rita Horvath, Claudia Gross, Nicolai Kohlschmidt, Fabian Förster, Angela Abicht, Anne Schänzer, Ulrike Schara-Schmidt, Andreas Roos, Adela Della Marina.
      The synthesis of cytochrome c oxidase 2 (SCO2) gene encodes for a mitochondrial located metallochaperone essential for the synthesis of the cytochrome c oxidase (COX) subunit 2. Recessive mutations in SCO2 have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency and in only four cases with axonal neuropathy. Here, we identified a homozygous pathogenic variant (c.361G>C; p.(Gly121Arg)) in SCO2 in two brothers with isolated axonal motor neuropathy. To address pathogenicity of the amino acid substitution, biochemical studies were performed and revealed increased level of the mutant SCO2-protein and a dysregulation of COX subunits in leukocytes and moreover unraveled decrease of proteins involved in the manifestation of neuropathies. Hence, our combined data strengthen the concept of SCO2 being causative for a very rare form of axonal neuropathy, expand its molecular genetic spectrum and provide first biochemical insights into the underlying pathophysiology. This article is protected by copyright. All rights reserved.
    Keywords:  Charcot-Marie-Tooth disease; axonal neuropathy; synthesis of cytochrome c oxidase 2 (SCO2); white blood cell proteomics
    DOI:  https://doi.org/10.1002/humu.24338
  7. Nat Commun. 2022 Feb 03. 13(1): 651
    Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
    Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.
      Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
    DOI:  https://doi.org/10.1038/s41467-022-28272-1
  8. Transl Cancer Res. 2020 Jun;9(6): 3854-3859
    Identification of polymorphisms in mitochondrial cytochrome c oxidase genes as risk factors for gastric cancer.
    Yingnan Wang, Hongcai Wang, Shice Yin, Jingjing Zhang, Ruixing Zhang, Zhanjun Guo.
       Background: Single nucleotide polymorphisms (SNPs) in the D-Loop region of mitochondrial DNA (mtDNA) have been implied in tumorigenesis of different types of tumors, but the associations involving polymorphisms in mtDNA coding regions still need to be clarified. This study aimed to identify SNPs of mitochondrial cytochrome c oxidase genes (MT-CO) in the occurrence of gastric cancer (GC).
    Methods: The MT-CO genes were sequenced between 170 GC patients and 174 matched healthy controls. The χ 2 test was used to analyze differences in SNP frequencies between the two groups.
    Results: The SNPs of MT-CO region were associated with the risk of GC. The genotype 9540T was significantly associated with an increased risk for GC (P=0.018), whereas 9548G was associated with a reduced risk (P=0.029).
    Conclusions: The SNPs in MT-CO genes were found to be risk biomarkers for GC. It may provide a novel insight into the molecular mechanism in GC tumorigenesis and progression.
    Keywords:  Gastric cancer (GC); mitochondrial DNA (mtDNA); mitochondrial cytochrome c oxidase (MT-CO)
    DOI:  https://doi.org/10.21037/tcr-19-2227
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