bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2018‒11‒25
fourteen papers selected by
Gavin McStay
Staffordshire University


  1. Hum Mol Genet. 2018 Dec 01. 27(23): 4135-4144
    Pacheu-Grau D, Callegari S, Emperador S, Thompson K, Aich A, Topol SE, Spencer EG, McFarland R, Ruiz-Pesini E, Torkamani A, Taylor RW, Montoya J, Rehling P.
      Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.
    DOI:  https://doi.org/10.1093/hmg/ddy305
  2. BMC Biol. 2018 Nov 22. 16(1): 141
    Petrů M, Wideman J, Moore K, Alcock F, Palmer T, Doležal P.
      BACKGROUND: Bacteria and mitochondria contain translocases that function to transport proteins across or insert proteins into their inner and outer membranes. Extant mitochondria retain some bacterial-derived translocases but have lost others. While BamA and YidC were integrated into general mitochondrial protein transport pathways (as Sam50 and Oxa1), the inner membrane TAT translocase, which uniquely transports folded proteins across the membrane, was retained sporadically across the eukaryote tree.RESULTS: We have identified mitochondrial TAT machinery in diverse eukaryotic lineages and define three different types of eukaryote-encoded TatABC-derived machineries (TatAC, TatBC and TatC-only). Here, we investigate TatAC and TatC-only machineries, which have not been studied previously. We show that mitochondria-encoded TatAC of the jakobid Andalucia godoyi represent the minimal functional pathway capable of substituting for the Escherichia coli TatABC complex and can transport at least one substrate. However, selected TatC-only machineries, from multiple eukaryotic lineages, were not capable of supporting the translocation of this substrate across the bacterial membrane. Despite the multiple losses of the TatC gene from the mitochondrial genome, the gene was never transferred to the cell nucleus. Although the major constraint preventing nuclear transfer of mitochondrial TatC is likely its high hydrophobicity, we show that in chloroplasts, such transfer of TatC was made possible due to modifications of the first transmembrane domain.
    CONCLUSIONS: At its origin, mitochondria inherited three inner membrane translocases Sec, TAT and Oxa1 (YidC) from its bacterial ancestor. Our work shows for the first time that mitochondrial TAT has likely retained its unique function of transporting folded proteins at least in those few eukaryotes with TatA and TatC subunits encoded in the mitochondrial genome. However, mitochondria, in contrast to chloroplasts, abandoned the machinery multiple times in evolution. The overall lower hydrophobicity of the Oxa1 protein was likely the main reason why this translocase was nearly universally retained in mitochondrial biogenesis pathways.
    Keywords:  Hydrophobicity; Mitochondrial evolution; Protein transport; TAT translocase
    DOI:  https://doi.org/10.1186/s12915-018-0607-3
  3. Adv Anat Embryol Cell Biol. 2018 Nov 23.
    Aw WC, Garvin MR, Ballard JWO.
      In this review, we provide evidence to suggest that the cost of specific mtDNA mutations can be influenced by exogenous factors. We focus on macronutrient-mitochondrial DNA interactions as factors that may differentially influence the consequences of a change as mitochondria must be flexible in its utilization of dietary proteins, carbohydrates, and fats. To understand this fundamental dynamic, we briefly discuss the energy processing pathways in mitochondria. Next, we explore the mitochondrial functions that are initiated during energy deficiency or when cells encounter cellular stress. We consider the anterograde response (nuclear control of mitochondrial function) and the retrograde response (nuclear changes in response to mitochondrial signaling) and how this mito-nuclear crosstalk may be influenced by exogenous factors such as temperature and diet. Finally, we employ Complex I of the mitochondrial electron transport system as a case study and discuss the potential role of the dietary macronutrient ratio as a strong selective force that may shape the frequencies of mitotypes in populations and species. We conclude that this underexplored field likely has implications in the fundamental disciplines of evolutionary biology and quantitative genetics and the more biomedical fields of nutrigenomics and pharmacogenomics.
    Keywords:  Fitness; Functional compensation; Metabolic flexibility
    DOI:  https://doi.org/10.1007/102_2018_2
  4. J Med Ethics. 2018 Nov 21. pii: medethics-2018-105060. [Epub ahead of print]
    Palacios-González C, Cavaliere G.
      In a recent paper - Lesbian motherhood and mitochondrial replacement techniques: reproductive freedom and genetic kinship - we argued that lesbian couples who wish to have children who are genetically related to both of them should be allowed access to mitochondrial replacement techniques (MRTs). Françoise Baylis wrote a reply to our paper -'No' to lesbian motherhood using human nuclear genome transfer- where she challenges our arguments on the use of MRTs by lesbian couples, and on MRTs more generally. In this reply we respond to her claims and further clarify our position.
    Keywords:  mitochondria; mitochondrial DNA diseases; mitochondrial donation; mitochondrial replacement techniques; mitochondrial replacement therapy; nuclear genome transfer; three person IVF
    DOI:  https://doi.org/10.1136/medethics-2018-105060
  5. PLoS Genet. 2018 Nov;14(11): e1007743
    Sokol AM, Uszczynska-Ratajczak B, Collins MM, Bazala M, Topf U, Lundegaard PR, Sugunan S, Guenther S, Kuenne C, Graumann J, Chan SSL, Stainier DYR, Chacinska A.
      Development and function of tissues and organs are powered by the activity of mitochondria. In humans, inherited genetic mutations that lead to progressive mitochondrial pathology often manifest during infancy and can lead to death, reflecting the indispensable nature of mitochondrial biogenesis and function. Here, we describe a zebrafish mutant for the gene mia40a (chchd4a), the life-essential homologue of the evolutionarily conserved Mia40 oxidoreductase which drives the biogenesis of cysteine-rich mitochondrial proteins. We report that mia40a mutant animals undergo progressive cellular respiration defects and develop enlarged mitochondria in skeletal muscles before their ultimate death at the larval stage. We generated a deep transcriptomic and proteomic resource that allowed us to identify abnormalities in the development and physiology of endodermal organs, in particular the liver and pancreas. We identify the acinar cells of the exocrine pancreas to be severely affected by mutations in the MIA pathway. Our data contribute to a better understanding of the molecular, cellular and organismal effects of mitochondrial deficiency, important for the accurate diagnosis and future treatment strategies of mitochondrial diseases.
    DOI:  https://doi.org/10.1371/journal.pgen.1007743
  6. Sci Rep. 2018 Nov 19. 8(1): 17043
    Guo L, Wang Q, Weng L, Hauser LA, Strawser CJ, Mesaros C, Lynch DR, Blair IA.
      Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1-210; isoform A) expressed in the cytosol of cells rapidly translocates to the mitochondria, where it is converted to the mature form (81-210) by mitochondrial processing peptidase. Mature frataxin (81-210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for the devastating rare genetic disease of Friedreich's ataxia. The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich's ataxia and monitor the efficacy of therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41598-018-35346-y
  7. Antioxid Redox Signal. 2018 Nov 18.
    Villanueva R, Romero-Tamayo S, Laplaza R, Martínez-Oliván J, Velazquez-Campoy A, Sancho J, Ferreira P, Medina M.
      AIMS: The Human apoptosis-inducingfactor (hAIF) supports OXPHOS biogenesis and programmed cell death, with missense mutations producing neurodegenerative phenotypes. hAIF senses the redox environment of cellular compartments, stabilizing a charge-transfer complex (CTC) dimer that modulates the protein interaction network. In this context we aimed to evaluate the subcellular pH, CTC formation, and pathogenic mutations effects on hAIF stability, and a thermal denaturation high-throughput screening (HTS) assay to discover AIF binders.RESULTS: Apoptotic hAIF∆1-101 is not stable at intermembrane space (IMS) pH, but the 77-101 residues confer stability to the mitochondrial isoform. hAIF and its CTC populate different conformational ensembles with redox switch to the CTC producing a less stable and compact protein. The pathogenic G308E, R201 and E493V mutations modulate hAIF stability; particularly, R201 causes a population shift to a less stable conformation that remodels the active site structure and dynamics. We have identified new molecules that modulate the hAIF NADH/NAD+ association/dissociation equilibrium and regulate its catalytic efficiency.
    INNOVATION: Biophysical methods allow evaluating the regulation of hAIF functional ensembles and to develop an HTS assay to discover small molecules that might modulate hAIF stability and activities.
    CONCLUSION: The mitochondrial soluble 54-77 portion stabilizes hAIF at the IMS pH. NADH-redox linked conformational changes course with strong NAD+ binding and protein dimerization, but they produce a negative impact in overall hAIF stability. Loss of functionality in the R201 deletion is due to distortion of the active site architecture. We report molecules that may serve as leads in the development of hAIF bioactive compound.
    DOI:  https://doi.org/10.1089/ars.2018.7658
  8. Cell Rep. 2018 Nov 20. pii: S2211-1247(18)31687-5. [Epub ahead of print]25(8): 2036-2043.e5
    Opaliński Ł, Song J, Priesnitz C, Wenz LS, Oeljeklaus S, Warscheid B, Pfanner N, Becker T.
      Mitochondria possess elaborate machineries for the import of proteins from the cytosol. Cytosolic factors like Hsp70 chaperones and their co-chaperones, the J-proteins, guide proteins to the mitochondrial surface. The translocase of the mitochondrial outer membrane (TOM) forms the entry gate for preproteins. How the proteins are delivered to mitochondrial preprotein receptors is poorly understood. We identify the cytosolic J-protein Xdj1 as a specific interaction partner of the central receptor Tom22. Tom22 recruits Xdj1 to the mitochondrial surface to promote import of preproteins and assembly of the TOM complex. Additionally, we find that the receptor Tom70 binds a different cytosolic J-protein, Djp1. Our findings suggest that cytosolic J-proteins target distinct TOM receptors and promote the biogenesis of mitochondrial proteins.
    Keywords:  J-proteins; TOM complex; cytosolic chaperones; mitochondria; protein targeting
    DOI:  https://doi.org/10.1016/j.celrep.2018.10.083
  9. Nat Rev Neurol. 2018 Nov 19.
    Rahman S, Copeland WC.
      The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.
    DOI:  https://doi.org/10.1038/s41582-018-0101-0
  10. Cancer Metastasis Rev. 2018 Nov 17.
    Herst PM, Grasso C, Berridge MV.
      Tumor initiation, progression, and metastasis are tissue context-dependent processes. Cellular and non-cellular factors provide the selective microenvironment that determines the fate of the evolving tumor through mechanisms that include metabolic reprogramming. Genetic and epigenetic changes contribute to this reprogramming process, which is orchestrated through ongoing communication between the mitochondrial and nuclear genomes. Metabolic flexibility, in particular the ability to rapidly adjust the balance between glycolytic and mitochondrial energy production, is a hallmark of aggressive, invasive, and metastatic cancers. Tumor cells sustain damage to both nuclear and mitochondrial DNA during tumorigenesis and as a consequence of anticancer treatments. Nuclear and mitochondrial DNA mutations and polymorphisms are increasingly recognized as factors that influence metabolic reprogramming, tumorigenesis, and tumor progression. Severe mitochondrial DNA damage compromises mitochondrial respiration. When mitochondrial respiration drops below a cell-specific threshold, metabolic reprogramming and plasticity fail to compensate and tumor formation is compromised. In these scenarios, tumorigenesis can be restored by acquisition of respiring mitochondria from surrounding stromal cells. Thus, intercellular mitochondrial transfer has the potential to confer treatment resistance and to promote tumor progression and metastasis. Understanding the constraints of metabolic, and in particular bioenergetic reprogramming, and the role of intercellular mitochondrial transfer in tumorigenesis provides new insights into addressing tumor progression and treatment resistance in highly aggressive cancers.
    Keywords:  Glycolysis; Intercellular mitochondrial transfer; Metabolic reprogramming; Mitochondrial DNA; Respiration
    DOI:  https://doi.org/10.1007/s10555-018-9769-2
  11. PLoS Genet. 2018 Nov 19. 14(11): e1007805
    Samstag CL, Hoekstra JG, Huang CH, Chaisson MJ, Youle RJ, Kennedy SR, Pallanck LJ.
      Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading-deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved-site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis.
    DOI:  https://doi.org/10.1371/journal.pgen.1007805
  12. J Hum Genet. 2018 Nov 21.
    Murayama K, Shimura M, Liu Z, Okazaki Y, Ohtake A.
      Mitochondrial diseases are inherited metabolic diseases based on disorders of energy production. The expansion of exome analyses has led to the discovery of many pathogenic nuclear genes associated with these diseases, and research into the pathogenesis of metabolic diseases has progressed. In cases of Leigh syndrome, it is desirable to perform both biochemical and genetic analyses, and pathogenic gene mutations have been identified in over half of the cases analyzed this way. Tandem mass screening and organic acid analyses of urine can sometimes provide important information that leads to the identification of pathogenic genes. Our comprehensive gene analyses have led to the discovery of several novel genes for mitochondrial diseases. Indeed, we reported that GTPBP3 and QRSL1 are involved in mitochondrial DNA maturation. In 2017, as a result of international collaboration, we also identified that mutations in ATAD3 and C1QBP cause mitochondrial disease. Given the varied pathogeneses, treatments for mitochondrial diseases should be specifically tailored to the mutated gene. Clinical trials of sodium pyruvate, 5-aminolevulinic acid with sodium ferrous citrate, and taurine as a treatment for mitochondrial disease have begun in Japan. Given that some mitochondrial diseases may respond well to certain treatments if the pathogenic gene can be identified, an early genetic diagnosis is crucial. Additionally, in Japan, prenatal diagnoses for mitochondrial diseases caused by nuclear genes have been achieved for genes shown to be pathogenic. Treatment and management approaches, including prenatal diagnoses, specifically tailored to the various phenotypes and pathologies of mitochondrial diseases are expected to become increasingly available.
    DOI:  https://doi.org/10.1038/s10038-018-0528-6
  13. Yonsei Med J. 2018 Dec;59(10): 1190-1196
    Lee SJ, Na JH, Han J, Lee YM.
      PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease.MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO).
    RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p<0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group.
    CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.
    Keywords:  Kearns-Sayre syndrome; Mitochondrial diseases; chronic progressive external ophthalmoplegia; ophthalmoplegia
    DOI:  https://doi.org/10.3349/ymj.2018.59.10.1190
  14. IEEE J Sel Top Quantum Electron. 2019 Jan-Feb;25(1):25(1): 7100312
    Lange F, Dunne L, Hale L, Tachtsidis I.
      We present a multiwavelength, multichannel, time-domain near-infrared spectroscopy system named MAESTROS. This instrument can measure absorption and scattering coefficients and can quantify the concentrations of oxy- and deoxy-haemoglobin ([HbO2], [HHb]), and oxidation state of cytochrome-c-oxidase ([oxCCO]). This system is composed of a supercontinuum laser source coupled with two acousto-optic tuneable filters. The light is collected by four photomultipliers tubes, connected to a router to redirect the signal to a single time-correlated single-photon counting card. The interface between the system and the tissue is based on optical fibres. This arrangement allows us to resolve up to 16 wavelengths, within the range of 650-900 nm, at a sampling rate compatible with the physiology (from 0.5 to 2 Hz). In this paper, we describe the system and assess its performance based on two specifically designed protocols for photon migration instruments, the basic instrument protocol and nEUROPt protocols, and on a well characterized liquid phantom based on Intralipid and water. Then, the ability to resolve [HbO2 ], [HHb], and [oxCCO] is demonstrated on a homogeneous liquid phantom, based on blood for [HbO2], [HHb], and yeast for [oxCCO]. In the future, the system could be used to monitor brain tissue physiology.
    Keywords:  Time domain measurements; biomedical engineering; laser biomedical applications; photomultipliers; scattering; spectroscopy
    DOI:  https://doi.org/10.1109/JSTQE.2018.2833205