bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒03‒08
sixteen papers selected by
Gavin McStay
Staffordshire University


  1. Biol Chem. 2020 Mar 01. pii: /j/bchm.just-accepted/hsz-2020-0112/hsz-2020-0112.xml. [Epub ahead of print]
    Franco LVR, Su CH, Tzagoloff A.
      The respiratory pathway of mitochondria is composed of four electron transfer complexes and the ATP synthase. In this article we review evidence from studies of Saccharomyces cerevisiae that both ATP synthase and cytochrome oxidase (COX) are assembled from independent modules that correspond to structurally and functionally identifiable components of each complex. Biogenesis of the respiratory chain requires a coordinate and balanced expression of gene products that become partner subunits of the same complex, but are encoded in the two physically separated genomes. Current evidence indicates that synthesis of two key mitochondrial encoded subunits of ATP synthase is regulated by the F1 module. Expression of COX1 that codes for a subunit of the COX catalytic core, is also regulated by a mechanism that restricts synthesis of this subunit to the availability of a nuclear-encoded translational activator. The respiratory chain must maintain a fixed stoichiometry of the component enzyme complexes during cell growth. We propose that high molecular weight complexes composed of Cox6, a subunit of cytochrome oxidase, and of the Atp9 subunit of ATP synthase, play a key role in establishing the ratio of the two complexes during their assembly.
    Keywords:  ATP synthase; Atp9; Cox6; Saccharomyces cerevisiae; cytochrome oxidase; mitochondrial biogenesis
    DOI:  https://doi.org/10.1515/hsz-2020-0112
  2. Mol Cell. 2020 Mar 05. pii: S1097-2765(20)30105-2. [Epub ahead of print]77(5): 1107-1123.e10
    Phu L, Rose CM, Tea JS, Wall CE, Verschueren E, Cheung TK, Kirkpatrick DS, Bingol B.
      Mitochondria import nearly their entire proteome from the cytoplasm by translocating precursor proteins through the translocase of the outer membrane (TOM) complex. Here, we show dynamic regulation of mitochondrial import by the ubiquitin system. Acute pharmacological inhibition or genetic ablation of the mitochondrial deubiquitinase (DUB) USP30 triggers accumulation of Ub-substrates that are normally localized inside the mitochondria. Mitochondrial import of USP30 substrates is impaired in USP30 knockout (KO) cells, suggesting that deubiquitination promotes efficient import. Upstream of USP30, the E3 ligase March5 ubiquitinates mitochondrial proteins whose eventual import depends on USP30. In USP30 KOs, exogenous March5 expression induces accumulation of unimported translocation intermediates that are degraded by the proteasomes. In USP30 KO mice, TOM subunits have reduced abundance across multiple tissues. Together these data highlight how protein import into a subcellular compartment can be regulated by ubiquitination and deubiquitination by E3 ligase and DUB machinery positioned at the gate.
    Keywords:  Deubiquitinase; E3 Ubiquitin Ligase; Mitochondria; Mitochondrial Import; TOM complex; Ubiquitin System
    DOI:  https://doi.org/10.1016/j.molcel.2020.02.012
  3. BMC Biol. 2020 Mar 02. 18(1): 22
    Gray MW, Burger G, Derelle R, Klimeš V, Leger MM, Sarrasin M, Vlček Č, Roger AJ, Eliáš M, Lang BF.
      BACKGROUND: Comparative analyses have indicated that the mitochondrion of the last eukaryotic common ancestor likely possessed all the key core structures and functions that are widely conserved throughout the domain Eucarya. To date, such studies have largely focused on animals, fungi, and land plants (primarily multicellular eukaryotes); relatively few mitochondrial proteomes from protists (primarily unicellular eukaryotic microbes) have been examined. To gauge the full extent of mitochondrial structural and functional complexity and to identify potential evolutionary trends in mitochondrial proteomes, more comprehensive explorations of phylogenetically diverse mitochondrial proteomes are required. In this regard, a key group is the jakobids, a clade of protists belonging to the eukaryotic supergroup Discoba, distinguished by having the most gene-rich and most bacteria-like mitochondrial genomes discovered to date.RESULTS: In this study, we assembled the draft nuclear genome sequence for the jakobid Andalucia godoyi and used a comprehensive in silico approach to infer the nucleus-encoded portion of the mitochondrial proteome of this protist, identifying 864 candidate mitochondrial proteins. The A. godoyi mitochondrial proteome has a complexity that parallels that of other eukaryotes, while exhibiting an unusually large number of ancestral features that have been lost particularly in opisthokont (animal and fungal) mitochondria. Notably, we find no evidence that the A. godoyi nuclear genome has or had a gene encoding a single-subunit, T3/T7 bacteriophage-like RNA polymerase, which functions as the mitochondrial transcriptase in all eukaryotes except the jakobids.
    CONCLUSIONS: As genome and mitochondrial proteome data have become more widely available, a strikingly punctuate phylogenetic distribution of different mitochondrial components has been revealed, emphasizing that the pathways of mitochondrial proteome evolution are likely complex and lineage-specific. Unraveling this complexity will require comprehensive comparative analyses of mitochondrial proteomes from a phylogenetically broad range of eukaryotes, especially protists. The systematic in silico approach described here offers a valuable adjunct to direct proteomic analysis (e.g., via mass spectrometry), particularly in cases where the latter approach is constrained by sample limitation or other practical considerations.
    Keywords:  Andalucia godoyi; Jakobids; Mitochondrial evolution; Mitochondrial genome; Mitochondrial proteome; Mitochondrion; Protist
    DOI:  https://doi.org/10.1186/s12915-020-0741-6
  4. Biochim Biophys Acta Bioenerg. 2020 Feb 29. pii: S0005-2728(20)30027-X. [Epub ahead of print] 148177
    Stephan K, Ott M.
      The mitochondrial bc1 complex plays an important role in mitochondrial respiration. It transfers electrons from ubiquinol to the soluble electron shuttle cytochrome c and thereby contributes to the proton motive force across the inner mitochondrial membrane. In the yeast Saccharomyces cerevisiae, each monomer consists of three catalytic and seven accessory subunits. The bc1 complex is an obligate homo-dimer in all systems. It is currently not known when exactly during the assembly dimerization occurs. In this study, we determined that the dimer formation is an early event. Specifically, dimerization is mediated by the interaction of a stable tetramer formed by the two Cor subunits, Cor1 and Cor2, that joins assembly intermediate II, containing the fully hemylated cytochrome b and the two small accessory proteins, Qcr7 and Qcr8. Addition of cytochrome c1 and Qcr6 can either occur concomitantly or independently of dimerization. These results reveal a strict order in assembly, where dimerization occurs after stabilization of co-factor acquisition by cytochrome b. Finally, assembly is completed by addition of the remaining subunits.
    Keywords:  Complex III assembly; Cytochrome b; Dimerization; Mitochondrial respiration; Oxidative phosphorylation; bc(1) complex
    DOI:  https://doi.org/10.1016/j.bbabio.2020.148177
  5. Ann Hum Genet. 2020 Mar 02.
    Kaur P, Sharma S, Kadavigere R, Girisha KM, Shukla A.
      Leigh syndrome is a clinically and radiologically heterogeneous condition with approximately 75 genes, nuclear and mitochondrial, known to be implicated in its pathogenesis. Leigh syndrome due to complex II deficiency constitutes 2% to 7% of these cases. Previously, nine individuals with Leigh syndrome have been reported with pathogenic variants in SDHB, which encodes for the iron-sulfur cluster subunit of mitochondrial respiratory chain complex II. The proband presented with Leigh syndrome. Exome sequencing revealed a homozygous missense variant p.(Ala102Thr) in SDHB. In silico protein modeling of the wild-type and mutant proteins showed potentially decreased protein stability. We hereby report another individual with Leigh syndrome due to SDHB-related mitochondrial complex II deficiency and review the phenotype and genotype associated with this condition.
    Keywords:  Leigh disease; SDHB; mitochondrial diseases; mitochondrial respiratory chain complex II; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/ahg.12377
  6. Elife. 2020 Mar 02. pii: e51065. [Epub ahead of print]9
    Metzger MB, Scales JL, Dunklebarger MF, Loncarek J, Weissman AM.
      Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins. However, quality control (QC) pathways for misfolded mitochondrial proteins remain poorly-defined. Here, we establish temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts- proteins sen2-1HAts and sam35-2HAts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HAts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HAts is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires SSA family HSP70s and the HSP40 Sis1, providing the first evidence for chaperone involvement in MAD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex, Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. This study reveals a unique QC pathway comprised of a combination of cytosolic and mitochondrial factors that distinguish it from other cellular QC pathways.
    Keywords:  S. cerevisiae; cell biology
    DOI:  https://doi.org/10.7554/eLife.51065
  7. Biol Chem. 2020 Mar 01. pii: /j/bchm.just-accepted/hsz-2020-0104/hsz-2020-0104.xml. [Epub ahead of print]
    Bausewein T, Naveed H, Liang J, Nussberger S.
      In the past three decades, significant advances have been made in providing the biochemical background of TOM-mediated protein translocation into mitochondria. In the light of recent cryoelectron microscopy-derived structures of TOM isolated from Neurospora crassa and Saccharomyces cerevisiae, the interpretation of biochemical and biophysical studies of TOMmediated protein transport into mitochondria now rests on a solid basis. In this review, we compare the sub-nanometer structure of N. crassa TOM core complex with that of yeast. Both structures reveal remarkably well-conserved symmetrical dimers of ten membrane protein subunits. The structural data also validate predictions of weakly stable regions in the transmembrane β-barrel domains of the protein-conducting subunit Tom40, which signal the existence of β-strands located in interfaces of protein-protein interactions.
    Keywords:  TOM complex; cryo-EM; mitochondria; protein translocation; protein-conducting channel; β-barrel energetics
    DOI:  https://doi.org/10.1515/hsz-2020-0104
  8. Cell Rep. 2020 Mar 03. pii: S2211-1247(20)30192-3. [Epub ahead of print]30(9): 3092-3104.e4
    Caumont-Sarcos A, Moulin C, Poinot L, Guiard B, van der Laan M, Ieva R.
      Mitochondrial preproteins contain amino-terminal presequences directing them to the presequence translocase of the mitochondrial inner membrane (TIM23 complex). Depending on additional downstream import signals, TIM23 either inserts preproteins into the inner membrane or translocates them into the matrix. Matrix import requires the coupling of the presequence translocase-associated motor (PAM) to TIM23. The molecular mechanisms coordinating preprotein recognition by TIM23 in the intermembrane space (IMS) with PAM activation in the matrix are unknown. Here we show that subsequent to presequence recognition in the IMS, the Tim50 matrix domain facilitates the recruitment of the coupling factor Pam17. Next, the IMS domain of Tim50 promotes PAM recruitment to TIM23. Finally, the Tim50 transmembrane segment stimulates the matrix-directed import-driving force exerted by PAM. We propose that recognition of preprotein segments in the IMS and transfer of signal information across the inner membrane by Tim50 determine import motor activation.
    Keywords:  Pam17; TIM23; Tim50; import motor; mitochondria; mitochondrial Hsp70; preprotein import; presequence translocase
    DOI:  https://doi.org/10.1016/j.celrep.2020.02.031
  9. Genet Mol Biol. 2020 ;pii: S1415-47572020000200308. [Epub ahead of print]43(1 suppl. 1): e20190095
    Chiaratti MR, Macabelli CH, Augusto Neto JD, Grejo MP, Pandey AK, Perecin F, Collado MD.
      Given the major role of the mitochondrion in cellular homeostasis, dysfunctions of this organelle may lead to several common diseases in humans. Among these, maternal diseases linked to mitochondrial DNA (mtDNA) mutations are of special interest due to the unclear pattern of mitochondrial inheritance. Multiple copies of mtDNA are present in a cell, each encoding for 37 genes essential for mitochondrial function. In cases of mtDNA mutations, mitochondrial malfunctioning relies on mutation load, as mutant and wild-type molecules may co-exist within the cell. Since the mutation load associated with disease manifestation varies for different mutations and tissues, it is hard to predict the progeny phenotype based on mutation load in the progenitor. In addition, poorly understood mechanisms act in the female germline to prevent the accumulation of deleterious mtDNA in the following generations. In this review, we outline basic aspects of mitochondrial inheritance in mammals and how they may lead to maternally-inherited diseases. Furthermore, we discuss potential therapeutic strategies for these diseases, which may be used in the future to prevent their transmission.
    DOI:  https://doi.org/10.1590/1678-4685-GMB-2019-0095
  10. Biol Chem. 2019 Dec 01. pii: /j/bchm.just-accepted/hsz-2019-0444/hsz-2019-0444.xml. [Epub ahead of print]
    Schneider A.
      The evolution of mitochondrial protein import and the systems that mediate it marks the boundary between the endosymbiotic ancestor of mitochondria and a true organelle that is under the control of the nucleus. Protein import has been studied in great detail in Saccharomyces cerevisiae. More recently it has also been extensively investigated in the parasitic protozoan Trypanosoma brucei making it arguably the second best studied system. Here I provide a comparative analysis of the protein import complexes of yeast and trypanosomes. Together with data from other systems, this allows to reconstruct the ancestral features of import complexes that were present in the last eukaryotic common ancestor (LECA) and to identify which subunits were added later in evolution. I discuss how these data can be translated into plausible scenarios providing insights into the evolution of (i) outer membrane protein import receptors, (ii) proteins involved in biogenesis of α-helically anchored outer membrane proteins, and (iii) of the intermembrane space import and assembly system. Finally, I show that the unusual presequence-associated import motor of trypanosomes suggests a scenario of how the two ancestral inner membrane protein translocases present in LECA evolved into the single bifunctional one found in extant trypanosomes.
    Keywords:  LECA; TIM complex; TOM complex; membrane translocation; parasite; protein translocases
    DOI:  https://doi.org/10.1515/hsz-2019-0444
  11. NPJ Genom Med. 2020 ;5 7
    Slone J, Huang T.
      The recent success of gene therapy across multiple clinical trials has inspired a great deal of hope regarding the treatment of previously intractable genetic diseases. This optimism has been extended to the prospect of gene therapy for mitochondrial disorders, which are not only particularly severe but also difficult to treat. However, this hope must be tempered by the reality of the mitochondrial organelle, which possesses specific biological properties that complicate genetic manipulation. In this perspective, we will discuss some of these complicating factors, including the unique pathways used to express and import mitochondrial proteins. We will also present some ways in which these challenges can be overcome by genetic manipulation strategies tailored specifically for mitochondrial diseases.
    Keywords:  Diseases; Genetics research; Medical genetics
    DOI:  https://doi.org/10.1038/s41525-020-0116-5
  12. Biol Chem. 2020 Mar 01. pii: /j/bchm.just-accepted/hsz-2020-0106/hsz-2020-0106.xml. [Epub ahead of print]
    Mokranjac D.
      Biogenesis of mitochondria relies on import of over 1000 different proteins from the cytosol. About 70% of these proteins follow the presequence pathway - they are synthesized with cleavable N-terminal extensions called presequences and reach the final place of their function within the organelle with the help of the TOM and TIM23 complexes in the outer and inner membranes, respectively. The translocation of proteins along the presequence pathway is powered by the import motor of the TIM23 complex. The import motor of the TIM23 complex is localized at the matrix face of the inner membrane and is likely the most complicated Hsp70-based system identified to date. How it converts the energy of ATP hydrolysis into unidirectional translocation of proteins into mitochondria remains one of the biggest mysteries of this translocation pathway. Here, I discuss the knowns and the unknowns of the mitochondrial protein import motor.
    Keywords:  Hsp70; J protein; chaperone; mitochondria; protein translocation
    DOI:  https://doi.org/10.1515/hsz-2020-0106
  13. Commun Biol. 2020 Mar 05. 3(1): 99
    Nakamura S, Matsui A, Akabane S, Tamura Y, Hatano A, Miyano Y, Omote H, Kajikawa M, Maenaka K, Moriyama Y, Endo T, Oka T.
      LETM1 is a mitochondrial inner membrane protein that is required for maintaining the mitochondrial morphology and cristae structures, and regulates mitochondrial ion homeostasis. Here we report a role of LETM1 in the organization of cristae structures. We identified four amino acid residues of human LETM1 that are crucial for complementation of the growth deficiency caused by gene deletion of a yeast LETM1 orthologue. Substituting amino acid residues with alanine disrupts the correct assembly of a protein complex containing LETM1 and prevents changes in the mitochondrial morphology induced by exogenous LETM1 expression. Moreover, the LETM1 protein changes the shapes of the membranes of in vitro-reconstituted proteoliposomes, leading to the formation of invaginated membrane structures on artificial liposomes. LETM1 mutant proteins with alanine substitutions fail to facilitate the formation of invaginated membrane structures, suggesting that LETM1 plays a fundamental role in the organization of mitochondrial membrane morphology.
    DOI:  https://doi.org/10.1038/s42003-020-0832-5
  14. Nature. 2020 Mar 04.
    Fessler E, Eckl EM, Schmitt S, Mancilla IA, Meyer-Bender MF, Hanf M, Philippou-Massier J, Krebs S, Zischka H, Jae LT.
      Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies1-3. Mitochondrial malfunction needs to be relayed to the cytosol, where an integrated stress response is triggered by the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) in mammalian cells4,5. eIF2α phosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress6. However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown1,2,7. Here we combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. Together, these findings could be used to inform future strategies to modulate the cellular response to mitochondrial dysfunction in the context of human disease.
    DOI:  https://doi.org/10.1038/s41586-020-2076-4
  15. Front Plant Sci. 2020 ;11 64
    Lee DW, Lee S, Min CK, Park C, Kim JM, Hwang CS, Park SK, Cho NH, Hwang I.
      Plants have two endosymbiotic organelles, chloroplast and mitochondrion. Although they have their own genomes, proteome assembly in these organelles depends on the import of proteins encoded by the nuclear genome. Previously, we elucidated the general design principles of chloroplast and mitochondrial targeting signals, transit peptide, and presequence, respectively, which are highly diverse in primary structure. Both targeting signals are composed of N-terminal specificity domain and C-terminal translocation domain. Especially, the N-terminal specificity domain of mitochondrial presequences contains multiple arginine residues and hydrophobic sequence motif. In this study we investigated whether the design principles of plant mitochondrial presequences can be applied to those in other eukaryotic species. We provide evidence that both presequences and import mechanisms are remarkably conserved throughout the species. In addition, we present evidence that the N-terminal specificity domain of presequence might have evolved from the bacterial TAT (twin-arginine translocation) signal sequence.
    Keywords:  N-terminal specificity domain; TAT (twin-arginine translocation) signal sequence; chloroplast; evolution of endosymbiotic organelles; mitochondria; presequence; transit peptide
    DOI:  https://doi.org/10.3389/fpls.2020.00064
  16. PLoS Genet. 2020 Mar;16(3): e1008604
    Ferreira N, Andoniou CE, Perks KL, Ermer JA, Rudler DL, Rossetti G, Periyakaruppiah A, Wong JKY, Rackham O, Noakes PG, Degli-Esposti MA, Filipovska A.
      The influence of environmental insults on the onset and progression of mitochondrial diseases is unknown. To evaluate the effects of infection on mitochondrial disease we used a mouse model of Leigh Syndrome, where a missense mutation in the Taco1 gene results in the loss of the translation activator of cytochrome c oxidase subunit I (TACO1) protein. The mutation leads to an isolated complex IV deficiency that mimics the disease pathology observed in human patients with TACO1 mutations. We infected Taco1 mutant and wild-type mice with a murine cytomegalovirus and show that a common viral infection exacerbates the complex IV deficiency in a tissue-specific manner. We identified changes in neuromuscular morphology and tissue-specific regulation of the mammalian target of rapamycin pathway in response to viral infection. Taken together, we report for the first time that a common stress condition, such as viral infection, can exacerbate mitochondrial dysfunction in a genetic model of mitochondrial disease.
    DOI:  https://doi.org/10.1371/journal.pgen.1008604