bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2021‒01‒10
seven papers selected by
Gavin McStay
Staffordshire University
  1. Role of GTPases in Driving Mitoribosome Assembly.
  2. CRISPR/Cas9-mediated mutagenesis at microhomologous regions of human mitochondrial genome.
  3. Mitochondrial sorting and assembly machinery operates by β-barrel switching.
  4. Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1.
  5. Barth syndrome: cardiolipin, cellular pathophysiology, management, and novel therapeutic targets.
  6. Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase.
  7. Tune instead of destroy: How proteolysis keeps OXPHOS in shape.
  1. Trends Cell Biol. 2021 Jan 05. pii: S0962-8924(20)30254-3. [Epub ahead of print]
    Role of GTPases in Driving Mitoribosome Assembly.
    Priyanka Maiti, Elena Lavdovskaia, Antoni Barrientos, Ricarda Richter-Dennerlein.
      Mitoribosomes catalyze essential protein synthesis within mitochondria. Mitoribosome biogenesis is assisted by an increasing number of assembly factors, among which guanosine triphosphate hydrolases (GTPases) are the most abundant class. Here, we review recent progress in our understanding of mitoribosome assembly GTPases. We describe their shared and specific features and mechanisms of action, compare them with their bacterial counterparts, and discuss their possible roles in the assembly of small or large mitoribosomal subunits and the formation of the monosome by establishing quality-control checkpoints during these processes. Furthermore, following the recent unification of the nomenclature for the mitoribosomal proteins, we also propose a unified nomenclature for mitoribosome assembly GTPases.
    Keywords:  GTPBP; OXPHOS deficiency; mitochondrial diseases; mitochondrial ribosome; mitoribosome assembly GTPase; quality control of mitoribosome maturation
    DOI:  https://doi.org/10.1016/j.tcb.2020.12.008
  2. Sci China Life Sci. 2021 Jan 06.
    CRISPR/Cas9-mediated mutagenesis at microhomologous regions of human mitochondrial genome.
    Bang Wang, Xiujuan Lv, Yufei Wang, Zhibo Wang, Qi Liu, Bin Lu, Yong Liu, Feng Gu.
      Genetic manipulation of mitochondrial DNA (mtDNA) could be harnessed for deciphering the gene function of mitochondria; it also acts as a promising approach for the therapeutic correction of pathogenic mutation in mtDNA. However, there is still a lack of direct evidence showing the edited mutagenesis within human mtDNA by clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9). Here, using engineered CRISPR/Cas9, we observed numerous insertion/deletion (InDel) events at several mtDNA microhomologous regions, which were triggered specifically by double-strand break (DSB) lesions within mtDNA. InDel mutagenesis was significantly improved by sgRNA multiplexing and a DSB repair inhibitor, iniparib, demonstrating the evidence of rewiring DSB repair status to manipulate mtDNA using CRISPR/Cas9. These findings would provide novel insights into mtDNA mutagenesis and mitochondrial gene therapy for diseases involving pathogenic mtDNA.
    Keywords:  CRSIPR/Cas9; genome editing; microhomologous region; mtDNA
    DOI:  https://doi.org/10.1007/s11427-020-1819-8
  3. Nature. 2021 Jan 06.
    Mitochondrial sorting and assembly machinery operates by β-barrel switching.
    Hironori Takeda, Akihisa Tsutsumi, Tomohiro Nishizawa, Caroline Lindau, Jon V Busto, Lena-Sophie Wenz, Lars Ellenrieder, Kenichiro Imai, Sebastian P Straub, Waltraut Mossmann, Jian Qiu, Yu Yamamori, Kentaro Tomii, Junko Suzuki, Takeshi Murata, Satoshi Ogasawara, Osamu Nureki, Thomas Becker, Nikolaus Pfanner, Nils Wiedemann, Masahide Kikkawa, Toshiya Endo.
      The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior1-3. Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB)4-6. Here we use cryo-electron microscopy to determine the structures of two different forms of the yeast SAM complex at a resolution of 2.8-3.2 Å. The dimeric complex contains two copies of the β-barrel channel protein Sam50-Sam50a and Sam50b-with partially open lateral gates. The peripheral membrane proteins Sam35 and Sam37 cap the Sam50 channels from the cytosolic side, and are crucial for the structural and functional integrity of the dimeric complex. In the second complex, Sam50b is replaced by the β-barrel protein Mdm10. In cooperation with Sam50a, Sam37 recruits and traps Mdm10 by penetrating the interior of its laterally closed β-barrel from the cytosolic side. The substrate-loaded SAM complex contains one each of Sam50, Sam35 and Sam37, but neither Mdm10 nor a second Sam50, suggesting that Mdm10 and Sam50b function as placeholders for a β-barrel substrate released from Sam50a. Our proposed mechanism for dynamic switching of β-barrel subunits and substrate explains how entire precursor proteins can fold in association with the mitochondrial machinery for β-barrel assembly.
    DOI:  https://doi.org/10.1038/s41586-020-03113-7
  4. Front Cell Dev Biol. 2020 ;8 603688
    Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1.
    Chunhua Jiang, Balaji T Moorthy, Devang M Patel, Akhilesh Kumar, William M Morgan, Belkis Alfonso, Jingyu Huang, Theodore J Lampidis, Daniel G Isom, Antoni Barrientos, Flavia Fontanesi, Fangliang Zhang.
      Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the regulation of metabolism and apoptosis. Although mitochondria play relevant roles in these processes in health and disease, a causal relationship between ATE1 activity and mitochondrial biology has yet to be established. Here, we report a phylogenetic analysis that traces the roots of ATE1 to alpha-proteobacteria, the mitochondrion microbial ancestor. We then demonstrate that a small fraction of ATE1 localizes within mitochondria. Furthermore, the absence of ATE1 influences the levels, organization, and function of respiratory chain complexes in mouse cells. Specifically, ATE1-KO mouse embryonic fibroblasts have increased levels of respiratory supercomplexes I+III2+IVn. However, they have decreased mitochondrial respiration owing to severely lowered complex II levels, which leads to accumulation of succinate and downstream metabolic effects. Taken together, our findings establish a novel pathway for mitochondrial function regulation that might explain ATE1-dependent effects in various disease conditions, including cancer and aging, in which metabolic shifts are part of the pathogenic or deleterious underlying mechanism.
    Keywords:  arginylation; arginyltransferase; biogenesis; mitochondria; respiration; respiratory chain complexes
    DOI:  https://doi.org/10.3389/fcell.2020.603688
  5. Mol Cell Biochem. 2021 Jan 07.
    Barth syndrome: cardiolipin, cellular pathophysiology, management, and novel therapeutic targets.
    Hana M Zegallai, Grant M Hatch.
      Barth syndrome is a rare X-linked genetic disease classically characterized by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia, and 3-methylglutaconic aciduria. It is caused by mutations in the tafazzin gene localized to chromosome Xq28.12. Mutations in tafazzin may result in alterations in the level and molecular composition of the mitochondrial phospholipid cardiolipin and result in large elevations in the lysophospholipid monolysocardiolipin. The increased monolysocardiolipin:cardiolipin ratio in blood is diagnostic for the disease, and it leads to disruption in mitochondrial bioenergetics. In this review, we discuss cardiolipin structure, synthesis, and function and provide an overview of the clinical and cellular pathophysiology of Barth Syndrome. We highlight known pharmacological management for treatment of the major pathological features associated with the disease. In addition, we discuss non-pharmacological management. Finally, we highlight the most recent promising therapeutic options for this rare mitochondrial disease including lipid replacement therapy, peroxisome proliferator-activated receptor agonists, tafazzin gene replacement therapy, induced pluripotent stem cells, mitochondria-targeted antioxidants and peptides, and the polyphenolic compound resveratrol.
    Keywords:  Barth syndrome; Cardiolipin; Cholesterol; Genetic disease; Heart; Mitochondria; Neutropenia; Pharmacological management; Resveratrol; Skeletal muscle; Tafazzin
    DOI:  https://doi.org/10.1007/s11010-020-04021-0
  6. Environ Pollut. 2020 Dec 28. pii: S0269-7491(20)37066-4. [Epub ahead of print]271 116377
    Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase.
    Libing Yu, Wenjing Li, Jian Chu, Chun Chen, Xijian Li, Wei Tang, Binyuan Xia, Zhonghua Xiong.
      As an emerging pollutant, uranium poses serious concerns to ecological and human health. The kidney has been established as a major deposition site and the most sensitive target organ for uranium poisoning, and the underlying toxicological mechanisms have been associated with oxidative stress and mitochondrial respiration. However, the identities of key molecular targets in uranium-induced toxicity remain elusive. In this study, we comprehensively evaluated the in vitro effects of uranium on ten critical enzymes in the mitochondrial respiration pathway and discovered that respiratory chain complex IV (cytochrome c oxidase) and complex V (ATP synthase) were strongly inhibited. The inhibitory effects were validated with mitochondria from human renal proximal tubule cells-the most affected renal site in uranium poisoning. The IC50 values (around 1 mg/L) are physiologically relevant, as they are comparable to known kidney accumulation levels in uranium poisoning. In addition, these inhibitory effects could explain the well-documented uranium-induced reactive oxygen species generation and mitochondrial alterations. In conclusion, cytochrome c oxidase and ATP synthase are possibly key molecular targets underlying the toxic effects of uranium.
    Keywords:  ATP synthase; Cytochrome c oxidase; Mitochondria; Respiratory chain complex; Uranium
    DOI:  https://doi.org/10.1016/j.envpol.2020.116377
  7. Biochim Biophys Acta Bioenerg. 2021 Jan 05. pii: S0005-2728(20)30215-2. [Epub ahead of print] 148365
    Tune instead of destroy: How proteolysis keeps OXPHOS in shape.
    Karolina Szczepanowska, Aleksandra Trifunovic.
      Mitochondria are highly dynamic and stress-responsive organelles that are renewed, maintained and removed by a number of different mechanisms. Recent findings bring more evidence for the focused, defined, and regulatory function of the intramitochondrial proteases extending far beyond the traditional concepts of damage control and stress responses. Until recently, the macrodegradation processes, such as mitophagy, were promoted as the major regulator of OXPHOS remodelling and turnover. However, the spatiotemporal dynamics of the OXPHOS system can be greatly modulated by the intrinsic mitochondrial mechanisms acting apart from changes in the global mitochondrial dynamics. This, in turn, may substantially contribute to the shaping of the metabolic status of the cell.
    Keywords:  Mitochondrial respiratory chain; OXPHOS maintanance; OXPHOS turnover; mitochondrial proteases
    DOI:  https://doi.org/10.1016/j.bbabio.2020.148365
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