bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒03‒01
twelve papers selected by
Gavin McStay
Staffordshire University


  1. Biochim Biophys Acta Mol Basis Dis. 2020 Feb 24. pii: S0925-4439(20)30091-0. [Epub ahead of print] 165746
    Reinhardt C, Arena G, Nedara K, Edwards R, Brenner C, Tokatlidis K, Modjtahedi N.
      In the mitochondria of healthy cells, Apoptosis-Inducing factor (AIF) is required for the optimal functioning of the respiratory chain machinery, mitochondrial integrity, cell survival, and proliferation. In all analysed species, it was revealed that the downregulation or depletion of AIF provokes mainly the post-transcriptional loss of respiratory chain Complex I protein subunits. Recent progress in the field has revealed that AIF fulfils its mitochondrial pro-survival function by interacting physically and functionally with CHCHD4, the evolutionarily-conserved human homolog of yeast Mia40. The redox-regulated CHCHD4/Mia40-dependent import machinery operates in the intermembrane space of the mitochondrion and controls the import of a set of nuclear-encoded cysteine-motif carrying protein substrates. In addition to their participation in the biogenesis of specific respiratory chain protein subunits, CHCHD4/Mia40 substrates are also implicated in the control of redox regulation, antioxidant response, translation, lipid homeostasis and mitochondrial ultrastructure and dynamics. Here, we discuss recent insights on the AIF/CHCHD4-dependent protein import pathway and review current data concerning the CHCHD4/Mia40 protein substrates in metazoan. Recent findings and the identification of disease-associated mutations in AIF or in specific CHCHD4/Mia40 substrates have highlighted these proteins as potential therapeutic targets in a variety of human disorders.
    Keywords:  Disulfide relay system; Metabolism; Mitochondria; Mitochondrial protein import; Respiratory chain machinery
    DOI:  https://doi.org/10.1016/j.bbadis.2020.165746
  2. Int J Mol Sci. 2020 Feb 25. pii: E1555. [Epub ahead of print]21(5):
    Chapa-Dubocq XR, Rodríguez-Graciani KM, Guzmán-Hernández RA, Jang S, Brookes PS, Javadov S.
      : Mitochondrial respiratory chain supercomplexes (RCS), particularly, the respirasome, which contains complexes I, III, and IV, have been suggested to participate in facilitating electron transport, reducing the production of reactive oxygen species (ROS), and maintaining the structural integrity of individual electron transport chain (ETC) complexes. Disassembly of the RCS has been observed in Barth syndrome, neurodegenerative and cardiovascular diseases, diabetes mellitus, and aging. However, the physiological role of RCS in high energy-demanding tissues such as the heart remains unknown. This study elucidates the relationship between RCS assembly and cardiac function. Adult male Sprague Dawley rats underwent Langendorff retrograde perfusion in the presence and absence of ethanol, isopropanol, or rotenone (an ETC complex I inhibitor). We found that ethanol had no effects on cardiac function, whereas rotenone reduced heart contractility, which was not recovered when rotenone was excluded from the perfusion medium. Blue native polyacrylamide gel electrophoresis revealed significant reductions of respirasome levels in ethanol- or rotenone-treated groups compared to the control group. In addition, rotenone significantly increased while ethanol had no effect on mitochondrial ROS production. In isolated intact mitochondria in vitro, ethanol did not affect respirasome assembly; however, acetaldehyde, a byproduct of ethanol metabolism, induced dissociation of respirasome. Isopropanol, a secondary alcohol which was used as an alternative compound, had effects similar to ethanol on heart function, respirasome levels, and ROS production. In conclusion, ethanol and isopropanol reduced respirasome levels without any noticeable effect on cardiac parameters, and cardiac function is not susceptible to moderate reductions of RCS.
    Keywords:  ethanol; heart; mitochondria; respirasome; respiratory chain supercomplexes
    DOI:  https://doi.org/10.3390/ijms21051555
  3. Biochim Biophys Acta Mol Basis Dis. 2020 Feb 24. pii: S0925-4439(20)30089-2. [Epub ahead of print] 165744
    El-Hafidi M, Correa F, Zazueta C.
      Cardiolipin (CL) is an acidic phospholipid almost exclusively found in the inner mitochondrial membrane, that not only stabilizes the structure and function of individual components of the mitochondrial electron transport chain, but regulates relevant mitochondrial processes, like mitochondrial dynamics and cristae structure maintenance among others. Alterations in CL due to peroxidation, correlates with loss of such mitochondrial activities and disease progression. In this review it is recapitulated the current state of knowledge of the role of cardiolipin remodeling associated with mitochondrial dysfunction in metabolic and cardiovascular diseases.
    Keywords:  Cardiolipin; Metabolic diseases; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.bbadis.2020.165744
  4. EMBO Mol Med. 2020 Feb 28. e11589
    Steele H, Gomez-Duran A, Pyle A, Hopton S, Newman J, Stefanetti RJ, Charman SJ, Parikh JD, He L, Viscomi C, Jakovljevic DG, Hollingsworth KG, Robinson AJ, Taylor RW, Bottolo L, Horvath R, Chinnery PF.
      Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae.
    Keywords:  bezafibrate; metabolomics; mitochondrial DNA; mitochondrial disorder; mitochondrial encephalomyopathy
    DOI:  https://doi.org/10.15252/emmm.201911589
  5. Antioxid Redox Signal. 2020 Feb 26.
    Gonçalves AM, Pereira-Santos AR, Esteves AR, Cardoso SM, Empadinhas N.
      SIGNIFICANCE: Mitoribosomes are mitochondrial ribosomes that translate mitochondrial mRNA in the matrix. Mitoribosomes have evolved to translate 13 polypeptides that perform the oxidative phosphorylation pathway. Although a number of devastating diseases result from defects in this mitochondrial translation apparatus, most are associated with genetic mutations and little is known about allelopathic defects caused by antibiotics, toxins, or nonproteinogenic amino acids. Recent advances: The levels of mitochondrial ribosomal subunits 12S and 16S rRNA in cells/tissues from patients carrying mutations in these genes are closely associated to mitochondrial translation efficiency alterations and impaired activities of the oxidative phosphorylation (OXPHOS), as well as with the severity of clinical phenotypes. In recent decades, many studies revealed a prominent role of mitochondrial dysfunction in Parkinson's disease (PD), however, the involvement of mitoribosomes is unknown. Critical issue: Considering that mitoribosomal structure and function can determine the efficiency of OXPHOS and that an impaired mitochondrial respiratory chain is a common finding in PD, we argue that the mitoribosome may be key to disease onset. With this review, we comprehensively integrate the available knowledge on the composition, assembly and role of the mitoribosome in mitochondrial efficiency, reflecting on its possible involvement on the etiopathogenesis of this epidemic disease as an appealing research avenue.FUTURE DIRECTIONS: If a direct correlation between mitoribosome failure and PD pathology is demonstrated, these mitochondrial complexes will provide valuable early clinical markers and potentially attractive targets for the development of innovative PD-directed therapeutic agents.
    DOI:  https://doi.org/10.1089/ars.2019.7997
  6. J Intern Med. 2020 Feb 25.
    Viscomi C, Zeviani M.
      Mitochondrial diseases are extremely heterogeneous genetic conditions characterized by faulty oxidative phosphorylation (OxPhos). OxPhos deficiency can be the result of mutation in mtDNA genes, encoding either proteins (13 subunits of the mitochondrial complexes I, III, IV and V) or the tRNA and rRNA components of the in situ mtDNA translation. The remaining mitochondrial disease genes are in the nucleus, encoding proteins with a huge variety of functions, from structural subunits of the mitochondrial complexes, to factors involved in their formation and regulation, components of the mtDNA replication and expression machinery, biosynthetic enzymes for the biosynthesis or incorporation of prosthetic groups, components of the mitochondrial quality control and proteostasis, enzymes involved in the clearance of toxic compounds, factors involved in the formation of the lipid milieu, etc. These different functions represent potential targets for "general" therapeutic interventions, as they may be adapted to a number of different mitochondrial conditions. This is in contrast with "tailored", personalized therapeutic approaches, such as gene therapy, cell therapy and organ replacement, that can be useful only for individual conditions. This review will present the most recent concepts emerged from preclinical work and the attempts to translate them into the clinics. The common notion that mitochondrial disorders have no cure is currently challenged by a massive effort of scientists and clinicians, and we do expect that thanks to this intensive investigation work, tangible results for the development of strategies amenable to the treatment of patients with these tremendously difficult conditions are not so far away.
    DOI:  https://doi.org/10.1111/joim.13046
  7. J Exp Zool A Ecol Integr Physiol. 2020 Feb 29.
    Chapdelaine V, Bettinazzi S, Breton S, Angers B.
      Activity of the oxidative phosphorylation complexes rely on intimately associated subunits encoded by the mitochondrial and nuclear genomes. Given the key role of this system in adenosine triphosphate production, genes from both genomes must coevolve. A combination of northern redbelly dace (Chrosomus eos) or finescale dace (C. neogaeus) mitochondrial genome with a C. eos nuclear genome allows for a close examination of a naturally occurring disruption of mitonuclear coevolution. We, therefore, investigated the combined effect of mitonuclear genotypes, acclimation, and temperature on the activity of enzymes linked with the energy metabolism in a sympatric population of wild type and cybrid. As expected, the activity of the nuclear-encoded citrate synthase was only influenced by temperature while the cytochrome c oxidase (composed of nuclear and mitochondrial subunits from wild type and cybrid individuals) responded differently to temperature. This study provides clear evidence of the extent by which mitonuclear coadaptation could influence aerobic metabolism.
    Keywords:  Chrosomus eos; cybrid; energetic metabolism; mitonuclear coevolution; northern redbelly dace; thermal acclimation; wild type
    DOI:  https://doi.org/10.1002/jez.2355
  8. Biol Chem. 2020 Feb 01. pii: /j/bchm.just-accepted/hsz-2020-0120/hsz-2020-0120.xml. [Epub ahead of print]
    Ohba Y, MacVicar T, Langer T.
      Mitochondria are multifaceted metabolic organelles and adapt dynamically to various developmental transitions and environmental challenges. The metabolic flexibility of mitochondria is provided by alterations in the mitochondrial proteome and is tightly coupled to changes in the shape of mitochondria. Mitochondrial proteases are emerging as important post-translational regulators of mitochondrial plasticity. The i-AAA protease YME1L, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, coordinates mitochondrial biogenesis and dynamics with the metabolic output of mitochondria. mTORC1 dependent lipid signalling drives proteolytic rewiring of mitochondria by YME1L. While the tissue-specific loss of YME1L in mice is associated with heart failure, disturbed eye development and axonal degeneration in the spinal cord, YME1L activity supports growth of pancreatic ductal adenocarcinoma cells. YME1L thus represents a key regulatory protease determining mitochondrial plasticity and metabolic reprogramming and is emerging as a promising therapeutic target.
    Keywords:  Lipin1; YME1L; cancer; i-AAA protease; mTORC1; mitochondria; mitochondrial plasticity; mitochondrial proteases
    DOI:  https://doi.org/10.1515/hsz-2020-0120
  9. Methods Mol Biol. 2020 ;2127 1-11
    Shaw PLR, Diederichs KA, Pitt A, Rollauer SE, Buchanan SK.
      Saccharomyces cerevisiae is a useful eukaryotic expression system for mitochondrial membrane proteins due to its ease of growth and ability to provide a native membrane environment. The development of the pBEVY vector system has further increased the potential of S. cerevisiae as an expression system by creating a method for expressing multiple proteins simultaneously. This vector system is amenable to the expression and purification of multi-subunit protein complexes. Here we describe the cloning, yeast transformation, and co-expression of multi-subunit outer mitochondrial membrane complexes using the pBEVY vector system.
    Keywords:  LiAc/SS transformation; Membrane protein complexes; Mitochondrial membrane protein; Multi-subunit expression; Saccharomyces cerevisiae; pBEVY
    DOI:  https://doi.org/10.1007/978-1-0716-0373-4_1
  10. Elife. 2020 Feb 27. pii: e52560. [Epub ahead of print]9
    von Känel C, Muñoz-Gómez SA, Oeljeklaus S, Wenger C, Warscheid B, Wideman JG, Harsman A, Schneider A.
      Many mitochondrial proteins contain N-terminal presequences that direct them to the organelle. The main driving force for their translocation across the inner membrane is provided by the presequence translocase-associated motor (PAM) which contains the J-protein Pam18. Here, we show that in the PAM of Trypanosoma brucei the function of Pam18 has been replaced by the non-orthologous euglenozoan-specific J-protein TbPam27. TbPam27 is specifically required for the import of mitochondrial presequence-containing but not for carrier proteins. Similar to yeast Pam18, TbPam27 requires an intact J-domain to function. Surprisingly, T. brucei still contains a bona fide Pam18 orthologue that, while essential for normal growth, is not involved in protein import. Thus, during evolution of kinetoplastids, Pam18 has been replaced by TbPam27. We propose that this replacement is linked to the transition from two ancestral and functionally distinct TIM complexes, found in most eukaryotes, to the single bifunctional TIM complex present in trypanosomes.
    Keywords:  biochemistry; chemical biology; evolutionary biology
    DOI:  https://doi.org/10.7554/eLife.52560
  11. Curr Opin Cell Biol. 2020 Feb 24. pii: S0955-0674(20)30007-7. [Epub ahead of print]63 162-173
    Funai K, Summers SA, Rutter J.
      The lipids that make up biological membranes tend to be the forgotten molecules of cell biology. The paucity of data on these important entities likely reflects the difficulties of studying and understanding their biological roles, rather than revealing a lack of importance. Indeed, the lipid composition of biological membranes has a profound impact on a diverse array of cellular processes. The focus of this review is on the effects of different lipid classes on the function of mitochondria, particularly bioenergetics, in health and disease.
    DOI:  https://doi.org/10.1016/j.ceb.2020.01.006
  12. Theranostics. 2020 ;10(5): 2141-2157
    Wang Q, Li M, Gan Y, Jiang S, Qiao J, Zhang W, Fan Y, Shen Y, Song Y, Meng Z, Yao M, Gu J, Zhang Z, Tu H.
      Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a malignant disease with a poor prognosis. One prominent aspect of PDAC that contributes to its aggressive behavior is its altered cellular metabolism. The aim of this study was to characterize the oncogenic effects of ubiquinol-cytochrome c reductase core protein I (UQCRC1), a key component of mitochondrial complex III, in PDAC development and to assess its potential as a therapeutic target for PDAC. Experimental Design: The expression of UQCRC1 in human PDAC tissues and p48-Cre/p53Flox/WT/LSL-KrasG12D (KPC) mouse pancreatic intraepithelial neoplasias (PanINs) was determined by immunohistochemistry. The role of UQCRC1 in promoting PDAC growth was evaluated in vitro in PANC-1 and CFPAC-1 cells and in vivo in transplanted mouse models of PDAC. Extracellular flux and RNA-Seq analyses were applied to investigate the mechanism of UQCRC1 in the regulation of mitochondrial metabolism and PDAC cell growth. The therapeutic potential of UQCRC1 in PDAC was assessed by knockdown of UQCRC1 using an RNA interference approach. Results: UQCRC1 expression showed a gradual increase during the progression from PanIN stages to PDAC in KPC mice. Elevated expression of UQCRC1 was observed in 72.3% of PDAC cases and was correlated with poor prognosis of the disease. UQCRC1 promoted PDAC cell growth in both in vitro experiments and in vivo subcutaneous and orthotopic mouse models. UQCRC1 overexpression resulted in increased mitochondrial oxidative phosphorylation (OXPHOS) and ATP production. The overproduced ATP was released into the extracellular space via the pannexin 1 channel and then functioned as an autocrine or paracrine agent to promote cell proliferation through the ATP/P2Y2-RTK/AKT axis. UQCRC1 knockdown or ATP release blockage could effectively inhibit PDAC growth. Conclusion: UQCRC1 has a protumor function and may serve as a potential prognostic marker and therapeutic target for PDAC.
    Keywords:  Extracellular ATP; Mitochondrial Oxidative Phosphorylation; Pancreatic Ductal Adenocarcinoma; UQCRC1
    DOI:  https://doi.org/10.7150/thno.38704