bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2021‒01‒17
seven papers selected by
Gavin McStay
Staffordshire University


  1. Mol Cell Proteomics. 2020 Jul;pii: S1535-9476(20)34978-1. [Epub ahead of print]19(7): 1145-1160
    Hock DH, Reljic B, Ang CS, Muellner-Wong L, Mountford HS, Compton AG, Ryan MT, Thorburn DR, Stroud DA.
      Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist in the membrane insertion of subunits, attachment of co-factors, and stabilization of assembly intermediates. The major fraction of complexes I, III and IV are present together in large molecular structures known as respiratory chain supercomplexes. Several assembly factors have been proposed as required for supercomplex assembly, including the hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines and extensive steady state, translation and affinity enrichment proteomics techniques we show that loss of HIGD2A leads to defects in the de novo biogenesis of mtDNA-encoded COX3, subsequent accumulation of complex IV intermediates and turnover of COX3 partner proteins. Deletion of HIGD2A also leads to defective complex IV activity. The impact of HIGD2A loss on complex IV was not altered by growth under hypoxic conditions, consistent with its role being in basal complex IV assembly. Although in the absence of HIGD2A we show that mitochondria do contain an altered supercomplex assembly, we demonstrate it to harbor a crippled complex IV lacking COX3. Our results redefine HIGD2A as a classical assembly factor required for building the COX3 module of complex IV.
    Keywords:  Mitochondria function or biology; OXPHOS; cytochrome c oxidase; energy metabolism; knockouts; mitochondria; mitochondrial disease; mtDNA translation; respirasome; translation
    DOI:  https://doi.org/10.1074/mcp.RA120.002076
  2. Mol Cell Proteomics. 2020 Jan;pii: S1535-9476(20)30006-2. [Epub ahead of print]19(1): 65-77
    Dibley MG, Formosa LE, Lyu B, Reljic B, McGann D, Muellner-Wong L, Kraus F, Sharpe AJ, Stroud DA, Ryan MT.
      NDUFAB1 is the mitochondrial acyl carrier protein (ACP) essential for cell viability. Through its pantetheine-4'-phosphate post-translational modification, NDUFAB1 interacts with members of the leucine-tyrosine-arginine motif (LYRM) protein family. Although several LYRM proteins have been described to participate in a variety of defined processes, the functions of others remain either partially or entirely unknown. We profiled the interaction network of NDUFAB1 to reveal associations with 9 known LYRM proteins as well as more than 20 other proteins involved in mitochondrial respiratory chain complex and mitochondrial ribosome assembly. Subsequent knockout and interaction network studies in human cells revealed the LYRM member AltMiD51 to be important for optimal assembly of the large mitoribosome subunit, consistent with recent structural studies. In addition, we used proteomics coupled with topographical heat-mapping to reveal that knockout of LYRM2 impairs assembly of the NADH-dehydrogenase module of complex I, leading to defects in cellular respiration. Together, this work adds to the catalogue of functions executed by LYRM family of proteins in building mitochondrial complexes and emphasizes the common and essential role of NDUFAB1 as a protagonist in mitochondrial metabolism.
    Keywords:  Mitochondria function or biology; acyl-carrier protein; affinity proteomics; blue native polyacrylamide gel electrophoresis; complex I; protein complex analysis; protein structure; protein-protein interactions
    DOI:  https://doi.org/10.1074/mcp.RA119.001784
  3. Int J Mol Sci. 2021 Jan 08. pii: E586. [Epub ahead of print]22(2):
    Protasoni M, Zeviani M.
      Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy production. The interest in this organelle has grown stronger with the discovery of their link to various pathologies, including cancer, aging and neurodegenerative diseases. Indeed, dysfunctional mitochondria cannot provide the required energy to tissues with a high-energy demand, such as heart, brain and muscles, leading to a large spectrum of clinical phenotypes. Mitochondrial defects are at the origin of a group of clinically heterogeneous pathologies, called mitochondrial diseases, with an incidence of 1 in 5000 live births. Primary mitochondrial diseases are associated with genetic mutations both in nuclear and mitochondrial DNA (mtDNA), affecting genes involved in every aspect of the organelle function. As a consequence, it is difficult to find a common cause for mitochondrial diseases and, subsequently, to offer a precise clinical definition of the pathology. Moreover, the complexity of this condition makes it challenging to identify possible therapies or drug targets.
    Keywords:  ATP production; biogenesis of the respiratory chain; mi-tochondrial electrochemical gradient; mitochondrial disease; mitochondrial potential; mitochondrial proton pumping; mitochondrial respiratory chain; oxidative phosphorylation; respiratory complex; respiratory supercomplex
    DOI:  https://doi.org/10.3390/ijms22020586
  4. Int J Mol Sci. 2021 Jan 07. pii: E551. [Epub ahead of print]22(2):
    Sendra L, García-Mares A, Herrero MJ, Aliño SF.
      Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.
    Keywords:  mitochondrial DNA; mitochondrial diseases; mitochondrial donation; mitochondrial replacement; three-parent baby
    DOI:  https://doi.org/10.3390/ijms22020551
  5. FEBS Lett. 2021 Jan 16.
    Gomez-Fabra Gala M, Vögtle FN.
      Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.
    Keywords:  Mitochondrial proteases; cancer; cardiomyopathy; mitochondrial protein biogenesis; mitochondrial protein quality control; neurodegeneration; proteostasis
    DOI:  https://doi.org/10.1002/1873-3468.14039
  6. J Transl Genet Genom. 2020 ;4 71-80
    Webb BD, Diaz GA, Prasun P.
      In eukaryotic cells, mitochondria perform the essential function of producing cellular energy in the form of ATP via the oxidative phosphorylation system. This system is composed of 5 multimeric protein complexes of which 13 protein subunits are encoded by the mitochondrial genome: Complex I (7 subunits), Complex III (1 subunit),Complex IV (3 subunits), and Complex (2 subunits). Effective mitochondrial translation is necessary to produce the protein subunits encoded by the mitochondrial genome (mtDNA). Defects in mitochondrial translation are known to cause a wide variety of clinical disease in humans with high-energy consuming organs generally most prominently affected. Here, we review several classes of disease resulting from defective mitochondrial translation including disorders with mitochondrial tRNA mutations, mitochondrial aminoacyl-tRNA synthetase disorders, mitochondrial rRNA mutations, and mitochondrial ribosomal protein disorders.
    Keywords:  Mitochondria; aminoacyl-tRNA synthetase; mitochondrial disease; mtDNA; rRNA; ribosomal protein; tRNA; translation defect
    DOI:  https://doi.org/10.20517/jtgg.2020.11
  7. Angew Chem Int Ed Engl. 2020 Dec 15.
    Giachin G, Jessop M, Bouverot R, Acajjaoui S, Saïdi M, Chretien A, Bacia-Verloop M, Signor L, Mas PJ, Favier A, Borel Meneroud E, Hons M, Hart DJ, Kandiah E, Boeri Erba E, Buisson A, Leonard G, Gutsche I, Soler-Lopez M.
      Fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are mitochondrial redox processes that generate ATP. The biogenesis of the respiratory Complex I, a 1 MDa multiprotein complex that is responsible for initiating OXPHOS, is mediated by assembly factors including the mitochondrial complex I assembly (MCIA) complex. However, the organisation and the role of the MCIA complex are still unclear. Here we show that ECSIT functions as the bridging node of the MCIA core complex. Furthermore, cryo-electron microscopy together with biochemical and biophysical experiments reveal that the C-terminal domain of ECSIT directly binds to the vestigial dehydrogenase domain of the FAO enzyme ACAD9 and induces its deflavination, switching ACAD9 from its role in FAO to an MCIA factor. These findings provide the structural basis for the MCIA complex architecture and suggest a unique molecular mechanism for coordinating the regulation of the FAO and OXPHOS pathways to ensure an efficient energy production.
    Keywords:  ACAD9; Cryo-EM; FAD; deflavination; mitochondrial complex I assembly complex
    DOI:  https://doi.org/10.1002/anie.202011548