bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2019–02–17
twenty-one papers selected by
Gavin McStay, Staffordshire University
  1. Mitochondrial Heterogeneity.
  2. MT-ATP6 Mitochondrial Disease Variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases.
  3. MELAS syndrome with m.4450 G > A mutation in mitochondrial tRNAMet gene.
  4. Late-onset mitochondrial disease in a patient with MELAS and mitochondrial DNA T14487C mutation.
  5. What the Cardiologist Should Know About Mitochondrial Cardiomyopathy?
  6. Mitochondrial disorders.
  7. Can Intestinal Pseudo-Obstruction Drive Recurrent Stroke-Like Episodes in Late-Onset MELAS Syndrome? A Case Report and Review of the Literature.
  8. 5' processing of Saccharomyces cerevisiae mitochondrial tRNAs requires expression of multiple genes.
  9. Mitochondrial Dysfunctions in Barth Syndrome.
  10. Double bonds of unsaturated fatty acids differentially regulate mitochondrial cardiolipin remodeling.
  11. A concert of RNA-binding proteins coordinates mitochondrial function.
  12. Msc6p is required for mitochondrial translation initiation in the absence of formylated Met-tRNAfmet.
  13. A mutagenesis analysis of Tim50, the major receptor of the TIM23 complex, identifies regions that affect its interaction with Tim23.
  14. Adult-onset Leigh syndrome linked to the novel stop codon mutation m.6579G>A in MT-CO1.
  15. Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions.
  16. Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.
  17. MtBrowse: An integrative genomics browser for human mitochondrial DNA.
  18. Mitochondrial DNA Fitness Depends on Nuclear Genetic Background in Drosophila.
  19. Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows.
  20. Leigh Syndrome: A Case Report with a Mitochondrial DNA Mutation.
  21. Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family.
  1. Front Genet. 2018 ;9 718
    Mitochondrial Heterogeneity.
    Juvid Aryaman, Iain G Johnston, Nick S Jones.
      Cell-to-cell heterogeneity drives a range of (patho)physiologically important phenomena, such as cell fate and chemotherapeutic resistance. The role of metabolism, and particularly of mitochondria, is increasingly being recognized as an important explanatory factor in cell-to-cell heterogeneity. Most eukaryotic cells possess a population of mitochondria, in the sense that mitochondrial DNA (mtDNA) is held in multiple copies per cell, where the sequence of each molecule can vary. Hence, intra-cellular mitochondrial heterogeneity is possible, which can induce inter-cellular mitochondrial heterogeneity, and may drive aspects of cellular noise. In this review, we discuss sources of mitochondrial heterogeneity (variations between mitochondria in the same cell, and mitochondrial variations between supposedly identical cells) from both genetic and non-genetic perspectives, and mitochondrial genotype-phenotype links. We discuss the apparent homeostasis of mtDNA copy number, the observation of pervasive intra-cellular mtDNA mutation (which is termed "microheteroplasmy"), and developments in the understanding of inter-cellular mtDNA mutation ("macroheteroplasmy"). We point to the relationship between mitochondrial supercomplexes, cristal structure, pH, and cardiolipin as a potential amplifier of the mitochondrial genotype-phenotype link. We also discuss mitochondrial membrane potential and networks as sources of mitochondrial heterogeneity, and their influence upon the mitochondrial genome. Finally, we revisit the idea of mitochondrial complementation as a means of dampening mitochondrial genotype-phenotype links in light of recent experimental developments. The diverse sources of mitochondrial heterogeneity, as well as their increasingly recognized role in contributing to cellular heterogeneity, highlights the need for future single-cell mitochondrial measurements in the context of cellular noise studies.
    Keywords:  cellular noise; complementation; heteroplasmy variance; macroheteroplasmy; microheteroplasmy; mitochondria
    DOI:  https://doi.org/10.3389/fgene.2018.00718
  2. Hum Mutat. 2019 Feb 14.
    MT-ATP6 Mitochondrial Disease Variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases.
    Rebecca D Ganetzky, Claudia Stendel, Elizabeth M McCormick, Zarazuela Zolkipli-Cunningham, Amy C Goldstein, Thomas Klopstock, Marni J Falk.
      Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G pathogenic variant in CV subunit gene, MT-ATP6, was among the first described human mitochondrial DNA (mtDNA) diseases. Due to a lack of clinically-available functional assays, validating the definitive pathogenicity of additional MT-ATP6 variants remains challenging. We reviewed all reported MT-ATP6 disease cases (n=218) to date, to assess for MT-ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings. We further describe the clinical and biochemical features of a new cohort of 14 kindreds with MT-ATP6 variants. Despite extensive overlap in the heteroplasmy levels of MT-ATP6 variant carriers with and without a wide range of clinical symptoms, previously reported symptomatic subjects had significantly higher heteroplasmy load (p=1.6x10-39 ). Pathogenic MT-ATP6 variants resulted in diverse biochemical features. The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, no single biochemical feature was universally observed. Extensive heterogeneity exists among both clinical and biochemical features of distinct MT-ATP6 variants. Improved mechanistic understanding and development of consistent biochemical diagnostic analyses are needed to permit accurate pathogenicity assessment of variants of uncertain significance in MT-ATP6. This article is protected by copyright. All rights reserved.
    Keywords:  Leigh Syndrome; Mitochondria; NARP, neurogenic ataxia and retinitis pigmentosa; genotype-phenotype correlation; heteroplasmy
    DOI:  https://doi.org/10.1002/humu.23723
  3. Brain Dev. 2019 Feb 07. pii: S0387-7604(18)30597-7. [Epub ahead of print]
    MELAS syndrome with m.4450 G > A mutation in mitochondrial tRNAMet gene.
    Mari Kuwajima, Masahide Goto, Koyuru Kurane, Hiroko Shimbo, Narumi Omika, Eriko F Jimbo, Kazuhiro Muramatsu, Makiko Tajika, Masaru Shimura, Kei Murayama, Kenji Kurosawa, Takanori Yamagata, Hitoshi Osaka.
      Mutations in the mitochondrial tRNAMet gene have been reported in only five patients to date, all of whom presented with muscle weakness and exercise intolerance as signs of myopathy. We herein report the case of a 12-year-old girl with focal epilepsy since the age of eight years. At age 11, the patient developed sudden visual disturbances and headaches accompanied by recurrent, stroke-like episodes with lactic acidosis (pH 7.279, lactic acid 11.6 mmol/L). The patient frequently developed a delirious state, exhibited regression of intellectual ability. Brain magnetic resonance imaging revealed high-intensity signals on T2-weighted images of the left occipital lobe. Mitochondrial gene analysis revealed a heteroplasmic m.4450G > A mutation in the mitochondrial tRNAMet. The heteroplasmic rate of the m.4450G > A mutation in blood, skin, urinary sediment, hair, saliva, and nail samples were 20, 38, 59, 41, 27, and 35%, respectively. The patient's fibroblast showed an approximately 53% reduction in the oxygen consumption rate, compared to a control, and decreased complex I and IV activities. Stroke-like episodes, lactic acidosis, encephalopathy with brain magnetic resonance imaging findings, and declined mitochondrial function were consistent with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. To our knowledge, the findings associated with this first patient with MELAS syndrome harboring the m.4450G > A mutation in mitochondrial tRNAMet expand the phenotypic spectrum of tRNAMet gene.
    Keywords:  Encephalopathy; Lactic acidosis; MELAS syndrome; MT-TM; m.4450G > A
    DOI:  https://doi.org/10.1016/j.braindev.2019.01.006
  4. Chin Med J (Engl). 2019 Feb 05.
    Late-onset mitochondrial disease in a patient with MELAS and mitochondrial DNA T14487C mutation.
    Xuebi Xu, Kunqian Ji, Jingwei Lv, Shu Zhang, Xiaoqing Lv, Chang Liu, Wei Li, Chuanzhu Yan, Yuying Zhao.
      We report a case of a 58-year-old male who presented with stroke-like episodes and late-onset mitochondrial encephalopathy. Brain magnetic resonance imaging (MRI) revealed multiple lesions in different locations, including in the left hypothalamus, bilateral parietal lobe, left occipital lobe, centrum semiovale and right cerebellar hemisphere. Muscle histopathological analysis showed no myopathic changes. We identified a T14487C mutation in the mitochondrial DNA (mtDNA), which causes a M63V substitution in the mitochondrial NADH dehydrogenase 6 (ND6) of complex I of the mitochondrial respiratory chain. The mutation was heteroplasmic in muscle and urine sediment with different mutation loads, and it was absent in the patient's blood sample. This case further expands the clinical spectrum associated with m.14487T>C mutation.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
    DOI:  https://doi.org/10.1097/CM9.0000000000000139
  5. Can J Cardiol. 2019 Feb;pii: S0828-282X(18)31308-4. [Epub ahead of print]35(2): 221-224
    What the Cardiologist Should Know About Mitochondrial Cardiomyopathy?
    Guillaume St-Pierre, Christian Steinberg, Michelle Dubois, Mario Sénéchal.
      Mitochondrial diseases are a heterogeneous group of rare hereditary disorders that may manifest with single organ involvement or as multisystemic disease. The pathophysiology of mitochondrial disease is complex and related to mutations of genes encoding mitochondrial proteins that are crucial to the cellular respiratory chain. Given its almost exclusive aerobic metabolism, the heart is particularly susceptible to mitochondrial dysfunction and commonly involved in mitochondrial disorders. Various clinical presentations are described, making clinical recognition challenging. Some patients may evolve towards the early need for heart transplantation, which emphasizes the importance of appropriate diagnosis and referral to a specialized centre.
    DOI:  https://doi.org/10.1016/j.cjca.2018.11.018
  6. Ann Transl Med. 2018 Dec;6(24): 475
    Mitochondrial disorders.
    Shibani Kanungo, Jacob Morton, Mekala Neelakantan, Kevin Ching, Jasmine Saeedian, Amy Goldstein.
      Primary mitochondrial disorders are a group of clinically variable and heterogeneous inborn errors of metabolism (IEMs), resulting from defects in cellular energy, and can affect every organ system of the body. Clinical presentations vary and may include symptoms of fatigue, skeletal muscle weakness, exercise intolerance, short stature, failure to thrive, blindness, ptosis and ophthalmoplegia, nystagmus, hearing loss, hypoglycemia, diabetes mellitus, learning difficulties, intellectual disability, seizures, stroke-like episodes, spasticity, dystonia, hypotonia, pain, neuropsychiatric symptoms, gastrointestinal reflux, dysmotility, gastrointestinal pseudo-obstruction, cardiomyopathy, cardiac conduction defects, and other endocrine, renal, cardiac, and liver problems. Most phenotypic manifestations are multi-systemic, with presentations varying at different age of onset and may show great variability within members of the same family; making these truly complex IEMs. Most primary mitochondrial diseases are autosomal recessive (AR); but maternally-inherited [from mitochondrial (mt) DNA], autosomal dominant and X-linked inheritance are also known. Mitochondria are unique energy-generating cellular organelles, geared for survival and contain their own unique genetic coding material, a circular piece of mtDNA about 16,000 base pairs in size. Additional nuclear (n)DNA encoded genes maintain mitochondrial biogenesis by supervising mtDNA replication, repair and synthesis, which is modified during increased energy demands or physiological stress. Despite our growing knowledge of the hundreds of genetic etiologies for this group of disorders, diagnosis can also remain elusive due to unique aspects of mitochondrial genetics. Though cure and FDA-approved therapies currently elude these IEMs, and current suggested therapies which include nutritional supplements and vitamins are of questionable efficacy; multi-center, international clinical trials are in progress for primary mitochondrial disorders.
    Keywords:  Mitochondria; energy metabolism; heteroplasmy; mtDNA; nDNA
    DOI:  https://doi.org/10.21037/atm.2018.12.13
  7. Front Neurol. 2019 ;10 38
    Can Intestinal Pseudo-Obstruction Drive Recurrent Stroke-Like Episodes in Late-Onset MELAS Syndrome? A Case Report and Review of the Literature.
    Delia Gagliardi, Eleonora Mauri, Francesca Magri, Daniele Velardo, Megi Meneri, Elena Abati, Roberta Brusa, Irene Faravelli, Daniela Piga, Dario Ronchi, Fabio Triulzi, Lorenzo Peverelli, Monica Sciacco, Nereo Bresolin, Giacomo Pietro Comi, Stefania Corti, Alessandra Govoni.
      Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder that is most commonly caused by the m. 3243A>G mutation in the MT-TL1 mitochondrial DNA gene, resulting in impairment of mitochondrial energy metabolism. Although childhood is the typical age of onset, a small fraction (1-6%) of individuals manifest the disease after 40 years of age and usually have a less aggressive disease course. The clinical manifestations are variable and mainly depend on the degree of heteroplasmy in the patient's tissues and organs. They include muscle weakness, diabetes, lactic acidemia, gastrointestinal disturbances, and stroke-like episodes, which are the most commonly observed symptom. We describe the case of a 50-year-old male patient who presented with relapsing intestinal pseudo-obstruction (IPO) episodes, which led to a late diagnosis of MELAS. After diagnosis, he presented several stroke-like episodes in a short time period and developed a rapidly progressive cognitive decline, which unfortunately resulted in his death. We describe the variable clinical manifestations of MELAS syndrome in this atypical and relatively old patient, with a focus on paralytic ileus and stroke-like episodes; the first symptom may have driven the others, leading to a relentless decline. Moreover, we provide a brief revision of previous reports of IPO occurrence in MELAS patients with the m.3243A>G mutation, and we investigate its relationship with stroke-like episodes. Our findings underscore the importance of recognizing gastrointestinal disturbance to prevent neurological comorbidities.
    Keywords:  MELAS; gastrointestinal disturbance; intestinal pseudo-obstruction; mitochondrial disorders; stroke-like episodes
    DOI:  https://doi.org/10.3389/fneur.2019.00038
  8. Biochim Biophys Acta Mol Cell Res. 2019 Feb 10. pii: S0167-4889(19)30010-2. [Epub ahead of print]
    5' processing of Saccharomyces cerevisiae mitochondrial tRNAs requires expression of multiple genes.
    Raquel F Guedes-Monteiro, Leticia V R Franco, Bruno S Moda, Alexander Tzagoloff, Mário H Barros.
      Mitochondrial tRNAs are processed at their 5'ends by highly divergent but ubiquitous RNase P. In Saccharomyces cerevisiae, Rpm2p is the protein component of RNase P. Here, we identify four novel genes MTA1, MTA2, GEP5 and PET130 of the Saccharomycetaceae family that are necessary for an efficient processing of mitochondrial tRNAs. Null mutants of mta1, mta2 and gep5 have severely reduced levels of mitochondrial tRNAs; in addition, temperature sensitive (ts) mutants of mta1, mta2, pet130 and gep5 accumulated tRNAs precursor transcripts at the restrictive but not at the permissive temperature. The same mitochondrial tRNAs precursors were also identified in rpm2 ts mutants or in the double ts mutants mta1 rpm2 and mta2 rpm2. The genetic and physical association of these four novel genes corroborate the hypothesis that they have their function associated. Different combinations of mta1, mta2, pet130 and gep5 ts alleles display a synthetic respiratory deficient phenotype, an indication of genetic interactions of the genes. Indeed, Mta1p, Mta2p, Pet130p, and Gep5p are associated with the mitochondrial inner membrane and are all extracted and sediment in sucrose gradients as high molecular weight complexes, where they may be present in a common complex with Rpm2p. This is supported by pull-down assays showing co-immunopurification of Rpm2 with Mta1p.
    Keywords:  Mitochondria; Processing; RNase P; tRNA
    DOI:  https://doi.org/10.1016/j.bbamcr.2019.02.002
  9. IUBMB Life. 2019 Feb 11.
    Mitochondrial Dysfunctions in Barth Syndrome.
    Sagnika Ghosh, Donna M Iadarola, Writoban Basu Ball, Vishal M Gohil.
      Barth syndrome (BTHS) is a rare multisystemic genetic disorder caused by mutations in the TAZ gene. TAZ encodes a mitochondrial enzyme that remodels the acyl chain composition of newly synthesized cardiolipin, a phospholipid unique to mitochondrial membranes. The clinical abnormalities observed in BTHS patients are caused by perturbations in various mitochondrial functions that rely on remodeled cardiolipin. However, the contribution of different cardiolipin-dependent mitochondrial functions to the pathology of BTHS is not fully understood. In this review, we will discuss recent findings from different genetic models of BTHS, including the yeast model of cardiolipin deficiency that has uncovered the specific in vivo roles of cardiolipin in mitochondrial respiratory chain biogenesis, bioenergetics, intermediary metabolism, mitochondrial dynamics, and quality control. We will also describe findings from higher eukaryotic models of BTHS that highlight a link between cardiolipin-dependent mitochondrial function and its impact on tissue and organ function. © 2019 IUBMB Life, 9999(9999):1-11, 2019.
    Keywords:  Barth syndrome; cardiolipin; mitochondria
    DOI:  https://doi.org/10.1002/iub.2018
  10. Lipids Health Dis. 2019 Feb 14. 18(1): 53
    Double bonds of unsaturated fatty acids differentially regulate mitochondrial cardiolipin remodeling.
    Hsiu-Chi Ting, Li-Tzu Chen, Jo-Yu Chen, Yi-Li Huang, Rui-Cheng Xin, Jui-Fen Chan, Yuan-Hao Howard Hsu.
       BACKGROUND: Supplemented fatty acids can incorporate into cardiolipin (CL) and affect its remodeling. The change in CL species may alter the mitochondrial membrane composition, potentially disturbing the mitochondrial structure and function during inflammation.
    METHOD: To investigate the effect of the unsaturation of fatty acids on CL, we supplemented macrophage-like RAW264.7 cells with 18-carbon unsaturated fatty acids including oleic acid (OA, 18:1), linoleic acid (LA, 18:2), α-linolenic acid (ALA, 18:3), γ-linolenic acid (GLA, 18:3), and stearidonic acid (SDA, 18:4). Mitochondrial changes in CL were measured through mass spectrometry.
    RESULT: Our data indicated that OA(18:1) was the most efficient fatty acid that incorporated into CL, forming symmetrical CL without fatty acid elongation and desaturation. In addition, LA(18:2) and ALA(18:3) were further elongated before incorporation, significantly increasing the number of double bonds and the chain length of CL. GLA and SDA were not optimal substrates for remodeling enzymes. The findings of RT-qPCR experiments revealed that none of these changes in CL occurred through the regulation of CL remodeling- or synthesis-related genes. The fatty acid desaturase and transportation genes-Fads2 and Cpt1a, respectively-were differentially regulated by the supplementation of five unsaturated 18-carbon fatty acids.
    CONCLUSIONS: The process of fatty acid incorporation to CL was regulated by the fatty acid desaturation and transportation into mitochondria in macrophage. The double bonds of fatty acids significantly affect the incorporation process and preference. Intact OA(18:1) was incorporated to CL; LA(18:2) and ALA(18:3) were desaturated and elongated to long chain fatty acid before the incorporation; GLA(18:3) and SDA(18:4) were unfavorable for the CL incorporation.
    Keywords:  18-carbon unsaturated fatty acids; Cardiolipin; Mass spectrometry; Mitochondrial membrane composition
    DOI:  https://doi.org/10.1186/s12944-019-0990-y
  11. Crit Rev Biochem Mol Biol. 2018 Dec;53(6): 652-666
    A concert of RNA-binding proteins coordinates mitochondrial function.
    Désirée Schatton, Elena I Rugarli.
      Mitochondria are dynamic and plastic organelles, which flexibly adapt morphology, ATP production, and metabolic function to meet extrinsic challenges and demands. Regulation of mitochondrial biogenesis is essential during development and in adult life to survive stress and pathological insults, and is achieved not only by increasing mitochondrial mass, but also by remodeling the organellar proteome, metabolome, and lipidome. In the last decade, the post-transcriptional regulation of the expression of nuclear-encoded mitochondrial proteins has emerged as a fast, flexible, and powerful mechanism to shape mitochondrial function and coordinate it with other cellular processes. At the heart of post-transcriptional responses are a number of RNA-binding proteins that specifically bind mRNAs encoding mitochondrial proteins and define their fate, by influencing transcript maturation, stability, translation, and localization. Thus, RNA-binding proteins provide a uniquely complex regulatory code that orchestrates mitochondrial function during physiological and pathological conditions.
    Keywords:  CLUH; Post-transcriptional regulation; Puf3; RNA regulon; localized translation
    DOI:  https://doi.org/10.1080/10409238.2018.1553927
  12. FEBS J. 2019 Feb 15.
    Msc6p is required for mitochondrial translation initiation in the absence of formylated Met-tRNAfmet.
    Leticia Veloso Ribeiro Franco, Bruno S Moda, Maria A K M Soares, Mario H Barros.
      Mitochondrial translation normally requires formylation of the initiator tRNA-met, a reaction catalyzed by the enzyme formyl transferase, Fmt1p and MTFMT in Saccharomyces cerevisiae and human mitochondria, respectively. Yeast fmt1 mutants devoid of Fmt1p, however, can synthesize all mitochondrial gene products by initiating translation with a non-formylated methionyl tRNA. Yeast synthetic respiratory-deficient fmt1 mutants have uncovered several factors suggested to play a role in translation initiation with non-formylated methionyl tRNA. Here, we present evidence that Msc6p, a member of the pentatricopeptide repeat (PPR) motif family, is another essential factor for mitochondrial translation in fmt1 mutants. The PPR motif is characteristic of RNA binding proteins found in chloroplasts and plant and fungal mitochondria, and is generally involved in RNA stability and transport. Moreover, in the present study we show that the respiratory deficiency of fmt1msc6 double mutants can be rescued by overexpression of the yeast mitochondrial initiation factor mIF-2, encoded by IFM1. The role of Msc6p in translational initiation is further supported by pull-down assays showing that it transiently interacts with mIF-2. Altogether, our data indicates that Msc6p is an important factor in mitochondrial translation with an auxiliary function related to the mIF-2-dependent formation of the initiation complex. This article is protected by copyright. All rights reserved.
    Keywords:   Saccharomyces cerevisiae ; Msc6p; mIF-2; mitochondrial translation; translational initiation
    DOI:  https://doi.org/10.1111/febs.14785
  13. Sci Rep. 2019 Feb 14. 9(1): 2012
    A mutagenesis analysis of Tim50, the major receptor of the TIM23 complex, identifies regions that affect its interaction with Tim23.
    Dana Dayan, May Bandel, Umut Günsel, Inbal Nussbaum, Gali Prag, Dejana Mokranjac, Walter Neupert, Abdussalam Azem.
      Maintenance of the mitochondrial proteome depends on import of newly made proteins from the cytosol. More than half of mitochondrial proteins are made as precursor proteins with N-terminal extensions called presequences and use the TIM23 complex for translocation into the matrix, the inner mitochondrial membrane and the intermembrane space (IMS). Tim50 is the central receptor of the complex that recognizes precursor proteins in the IMS. Additionally, Tim50 interacts with the IMS domain of the channel forming subunit, Tim23, an interaction that is essential for protein import across the mitochondrial inner membrane. In order to gain deeper insight into the molecular function of Tim50, we used random mutagenesis to determine residues that are important for its function. The temperature-sensitive mutants isolated were defective in import of TIM23-dependent precursor proteins. The residues mutated map to two distinct patches on the surface of Tim50. Notably, mutations in both patches impaired the interaction of Tim50 with Tim23. We propose that two regions of Tim50 play a role in its interaction with Tim23 and thereby affect the import function of the complex.
    DOI:  https://doi.org/10.1038/s41598-018-38353-1
  14. Mitochondrion. 2019 Feb 08. pii: S1567-7249(18)30175-2. [Epub ahead of print]
    Adult-onset Leigh syndrome linked to the novel stop codon mutation m.6579G>A in MT-CO1.
    Olivia V Poole, Chris M Everett, Sonia Gandhi, Silvia Marino, Enrico Bugiardini, Cathy Woodward, Amanda Lam, Ros Quinlivan, Michael G Hanna, Robert D S Pitceathly.
      Adult-onset Leigh syndrome is a rare but important manifestation of mitochondrial disease. We report a 17 year old female who presented with subacute encephalopathy, brainstem and extrapyramidal signs, raised CSF lactate, and symmetrical hyperintensities in the basal ganglia on T2-weighted cerebral MRI. The presence of cytochrome c oxidase deficient fibres in muscle tissue prompted sequencing of the entire mitochondrial genome which revealed the novel stop codon mutation m.6579G>A; p.Gly226X in MT-CO1. Here we present the case and review the clinicopathological and molecular spectrum of previously reported MT-CO1 truncating mutations.
    Keywords:  Cytochrome c oxidase; Leigh syndrome; MT-CO1
    DOI:  https://doi.org/10.1016/j.mito.2019.02.004
  15. Nat Commun. 2019 Feb 15. 10(1): 759
    Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions.
    Örjan Persson, Yazh Muthukumar, Swaraj Basu, Louise Jenninger, Jay P Uhler, Anna-Karin Berglund, Robert McFarland, Robert W Taylor, Claes M Gustafsson, Erik Larsson, Maria Falkenberg.
      Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.
    DOI:  https://doi.org/10.1038/s41467-019-08673-5
  16. Mol Cell. 2019 Jan 31. pii: S1097-2765(19)30003-6. [Epub ahead of print]
    Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.
    Haruka Sakaue, Takuya Shiota, Naoya Ishizaka, Shin Kawano, Yasushi Tamura, Kher Shing Tan, Kenichiro Imai, Chie Motono, Takatsugu Hirokawa, Kentaro Taki, Non Miyata, Osamu Kuge, Trevor Lithgow, Toshiya Endo.
      Mitochondria import nearly all of their resident proteins from the cytosol, and the TOM complex functions as their entry gate. The TOM complex undergoes a dynamic conversion between the majority population of a three-channel gateway ("trimer") and the minor population that lacks Tom22 and has only two Tom40 channels ("dimer"). Here, we found that the porin Por1 acts as a sink to bind newly imported Tom22. This Por1 association thereby modulates Tom22 integration into the TOM complex, guaranteeing formation of the functional trimeric TOM complex. Por1 sequestration of Tom22 dissociated from the trimeric TOM complex also enhances the dimeric TOM complex, which is preferable for the import of TIM40/MIA-dependent proteins into mitochondria. Furthermore, Por1 appears to contribute to cell-cycle-dependent variation of the functional trimeric TOM complex by chaperoning monomeric Tom22, which arises from the cell-cycle-controlled variation of phosphorylated Tom6.
    Keywords:  TOM complex; Tom22; Tom40; Tom6; VDAC; mitochondria; porin; protein import
    DOI:  https://doi.org/10.1016/j.molcel.2019.01.003
  17. Mitochondrion. 2019 Feb 06. pii: S1567-7249(18)30126-0. [Epub ahead of print]
    MtBrowse: An integrative genomics browser for human mitochondrial DNA.
    Vipin Singh, Bani Jolly, Neeraj K Rajput, Sayan Pramanik, Anshu Bhardwaj.
      The human mitochondrion is a unique semi-autonomous organelle with a genome of its own and also requires nuclear encoded components to carry out its functions. In addition to being the powerhouse of the cell, mitochondria plays a central role in several metabolic pathways. It is therefore challenging to delineate the cause-effect relationship in context of mitochondrial dysfunction. Several studies implicate mutations in mitochondrial DNA (mtDNA) in various complex diseases. The human mitochondrial DNA (mtDNA) encodes a set of 37 genes, 13 protein coding, 22 tRNAs and two ribosomal RNAs, which are essential structural and functional components of the electron transport chain. As mentioned above, variations in these genes have been implicated in a broad spectrum of diseases and are extensively reported in literature and various databases. A large number of databases and prediction methods have been published to elucidate the role of human mitochondrial DNA in various disease phenotypes. However, there is no centralized resource to visualize this genotype-phenotype data. Towards this, we have developed MtBrowse: an integrative genomics browser for human mtDNA. As of now, MtBrowse has four categories - Gene, Disease, Reported variation and Variation prediction. These categories have 105 tracks and house data on mitochondrial reference genes, around 600 variants reported in literature with respect to various disease phenotypes and predictions for potential pathogenic variations in protein-coding genes. MtBrowse also hosts genomic variation data from over 5000 individuals on 22 disease phenotypes. MtBrowse may be accessed at http://ab-openlab.csir.res.in/cgi-bin/gb2/gbrowse.
    DOI:  https://doi.org/10.1016/j.mito.2019.02.003
  18. G3 (Bethesda). 2019 Feb 11. pii: g3.400067.2019. [Epub ahead of print]
    Mitochondrial DNA Fitness Depends on Nuclear Genetic Background in Drosophila.
    Jim A Mossman, Jennifer Y Ge, Freddy Navarro, David M Rand.
      Mitochondrial DNA (mtDNA) has been one of the most extensively studied molecules in ecological, evolutionary and clinical genetics. In its early application in evolutionary genetics, mtDNA was assumed to be a selectively neutral marker conferring negligible fitness consequences for its host. However, this dogma has been overturned in recent years due to now extensive evidence for non-neutral evolutionary dynamics. Since mtDNA proteins physically interact with nuclear proteins to provide the mitochondrial machinery for aerobic ATP production, among other cell functions, co-variation of the respective genes is predicted to affect organismal fitness. To test this hypothesis we used an mtDNA-nuclear DNA introgression model in Drosophila melanogaster to test the fitness of genotypes in perturbation-reperturbation population cages and in a non-competitive assay for female fecundity. Genotypes consisted of both conspecific and heterospecific mtDNA-nDNA constructs, with either D. melanogaster or D. simulans mtDNAs on two alternative D. melanogaster nuclear backgrounds, to investigate mitonuclear genetic interactions (G × G effects). We found considerable variation between nuclear genetic backgrounds on the selection of mtDNA haplotypes. In addition, there was variation in the selection on mtDNAs pre- and post- reperturbation, demonstrating overall poor repeatability of selection. There was a strong influence of nuclear background on non-competitive fecundity across all the mtDNA species types. In only one of the four cage types did we see a significant fecundity effect between genotypes that could help explain the respective change in genotype frequency over generational time. We discuss these results in the context of G × G interactions and the possible influence of stochastic environments on mtDNA-nDNA selection.
    Keywords:  Drosophila; epistasis; fitness; haplotype; introgression; mitochondrial DNA; reperturbation cages
    DOI:  https://doi.org/10.1534/g3.119.400067
  19. Proc Natl Acad Sci U S A. 2019 Feb 13. pii: 201816556. [Epub ahead of print]
    Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows.
    Thorsten B Blum, Alexander Hahn, Thomas Meier, Karen M Davies, Werner Kühlbrandt.
      Mitochondrial ATP synthases form dimers, which assemble into long ribbons at the rims of the inner membrane cristae. We reconstituted detergent-purified mitochondrial ATP synthase dimers from the green algae Polytomella sp. and the yeast Yarrowia lipolytica into liposomes and examined them by electron cryotomography. Tomographic volumes revealed that ATP synthase dimers from both species self-assemble into rows and bend the lipid bilayer locally. The dimer rows and the induced degree of membrane curvature closely resemble those in the inner membrane cristae. Monomers of mitochondrial ATP synthase reconstituted into liposomes do not bend membrane visibly and do not form rows. No specific lipids or proteins other than ATP synthase dimers are required for row formation and membrane remodelling. Long rows of ATP synthase dimers are a conserved feature of mitochondrial inner membranes. They are required for cristae formation and a main factor in mitochondrial morphogenesis.
    Keywords:  ATP synthase; electron cryotomography; membrane curvature; mitochondria; subtomogram averaging
    DOI:  https://doi.org/10.1073/pnas.1816556116
  20. Rev Paul Pediatr. 2019 Jan-Mar;37(1):37(1): 136
    Leigh Syndrome: A Case Report with a Mitochondrial DNA Mutation.
    Anabela Oliveira Bandeira.
      
    DOI:  https://doi.org/10.1590/1984-0462/;2019;37;1;00020
  21. Front Cell Dev Biol. 2019 ;7 3
    Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family.
    Oluwaseun B Ogunbona, Steven M Claypool.
      The mitochondrial carrier family (MCF) is a group of transport proteins that are mostly localized to the inner mitochondrial membrane where they facilitate the movement of various solutes across the membrane. Although these carriers represent potential targets for therapeutic application and are repeatedly associated with human disease, research on the MCF has not progressed commensurate to their physiologic and pathophysiologic importance. Many of the 53 MCF members in humans are orphans and lack known transport substrates. Even for the relatively well-studied members of this family, such as the ADP/ATP carrier and the uncoupling protein, there exist fundamental gaps in our understanding of their biological roles including a clear rationale for the existence of multiple isoforms. Here, we briefly review this important family of mitochondrial carriers, provide a few salient examples of their diverse metabolic roles and disease associations, and then focus on an emerging link between several distinct MCF members, including the ADP/ATP carrier, and cytochrome c oxidase biogenesis. As the ADP/ATP carrier is regarded as the paradigm of the entire MCF, its newly established role in regulating translation of the mitochondrial genome highlights that we still have a lot to learn about these metabolite transporters.
    Keywords:  ADP/ATP carrier; cytochrome c oxidase; mitochondrial carrier family; mitochondrial translation; respiratory supercomplexes; solute carrier family
    DOI:  https://doi.org/10.3389/fcell.2019.00003
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