bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2017‒03‒19
seven papers selected by
Gavin McStay
New York Institute of Technology
  1. Mitochondrial DNA in pediatric leukemia patients.
  2. Kidney involvement in MELAS syndrome: Description of 2 cases.
  3. Resveratrol and Brain Mitochondria: a Review.
  4. MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content.
  5. Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML.
  6. Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression.
  7. The Novel Chloroplast Outer Membrane Kinase KOC1 Is a Required Component of the Plastid Protein Import Machinery.
  1. Acta Biochim Pol. 2017 Mar 09.
    Mitochondrial DNA in pediatric leukemia patients.
    Agata Kodroń, Magda Ghanim, Katarzyna K Krawczyk, Anna Stelmaszczyk-Emmel, Katarzyna Tońska, Urszula Demkow, Ewa Bartnik.
      Numerous studies of mitochondrial DNA (mtDNA) in cancer have shown differences between mtDNA sequences in tumor and normal tissue and at various stages of cancer treatment in the same patient. However, there is little data on acute lymphoblastic leukemia (ALL), the most common type of leukemia in children. In this study we compared mitochondrial sequence variation in the D-loop region and in 5 genes of mtDNA in bone marrow samples of 6 pediatric patients with ALL at various stages of therapy. We found several common polymorphisms and one variant at position 3688 whose level varied during leukemia treatment. Our results suggest that mitochondrial DNA mutations, whose levels change during patient treatment, could be potential biomarkers for monitoring treatment efficacy and disease progression.
    DOI:  https://doi.org/10.18388/abp.2016_1444
  2. Med Clin (Barc). 2017 Mar 07. pii: S0025-7753(17)30111-2. [Epub ahead of print]
    Kidney involvement in MELAS syndrome: Description of 2 cases.
    Pau Alcubilla-Prats, Manel Solé, Albert Botey, Josep Maria Grau, Glòria Garrabou, Esteban Poch.
      INTRODUCTION: MELAS syndrome -myopathy, encephalopathy, lactic acidosis and stroke-like episodes- is a maternally-inherited mitochondrial cytopathy related to several mitochondrial DNA mutations, with the A3243G mutation in tRNALeu gene being the most frequent of them.PATIENTS AND METHODS: Apart from its typical symptomatology, patients usually exhibit a maternally-inherited history of neurosensory deafness and insulin-dependent type 2 diabetes mellitus (T2DM). Recent studies have shown that few patients carrying a A3243G mutation also suffer from renal dysfunction, usually in form of focal segmental glomerulosclerosis (FSGS).
    RESULTS: In this study we examine kidney involvement in 2 unrelated patients with a A3243G mutation by genetic testing. Both have a maternally-inherited neurosensory deafness and insulin-dependent T2DM. A renal biopsy was performed in both patients. One patient developed nephrotic proteinuria and renal insufficiency, with FSGS findings being observed in the kidney biopsy, whereas the other suffered from mild proteinuria and renal insufficiency, with non-specific glomerular changes.
    CONCLUSION: The presence of FSGS or other kidney involvement accompanied by hereditary neurosensory deafness and T2DM could be suggestive of a A3243G tRNALeu mutation and should prompt a genetic testing and an evaluation of potential extrarenal involvement.
    Keywords:  A3243G mutation; Chronic kidney disease; Citopatía mitocondrial; Focal segmental glomerulosclerosis; Glomeruloesclerosis focal segmentaria; Insuficiencia renal crónica; Mitochondrial cythopathy; Mutación A3243G
    DOI:  https://doi.org/10.1016/j.medcli.2017.01.029
  3. Mol Neurobiol. 2017 Mar 10.
    Resveratrol and Brain Mitochondria: a Review.
    Fernanda Rafaela Jardim, Fernando Tonon de Rossi, Marielle Xavier Nascimento, Renata Gabriele da Silva Barros, Paula Agrizzi Borges, Isabella Cristina Prescilio, Marcos Roberto de Oliveira.
      Resveratrol (3,4',5-trihydroxystilbene; C14H12O3) is a polyphenolic phytoalexin found in grapes, berries, peanuts, and wines. Resveratrol has been viewed as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent. Moreover, it has been reported that resveratrol modulates mitochondrial function, redox biology, and dynamics in both in vitro and in vivo experimental models. Resveratrol also attenuates mitochondrial impairment induced by certain stressors. Resveratrol upregulates, for example, mitochondria-located antioxidant enzymes, decreasing the production of reactive species by these organelles. Resveratrol also triggers mitochondrial biogenesis, ameliorating the mitochondria-related bioenergetics status in mammalian cells. In the present work, we discuss about the effects of resveratrol on brain mitochondria. Brain cells (both neuronal and glial) are susceptible to mitochondrial dysfunction due to their high demand for adenosine triphosphate (ATP). Additionally, brain cells consume oxygen (O2) at very high rates, leading to a proportionally high mitochondrial production of reactive species. Therefore, strategies focusing on the maintenance of mitochondrial function in these cell types are of pharmacological interest in the case of neurodegenerative diseases, which involve mitochondrial impairment and increased generation of reactive species, leading to neuroinflammation and cell death. The mechanism by which resveratrol protects mitochondrial function and dynamics is not completely understood, and further research would be necessary in order to investigate exactly how resveratrol affects mitochondria-related parameters. Furthermore, it is particularly important because resveratrol is able to induce cytotoxicity depending on its dosage.
    Keywords:  Brain; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Redox biology; Resveratrol
    DOI:  https://doi.org/10.1007/s12035-017-0448-z
  4. Redox Biol. 2017 Mar 02. pii: S2213-2317(16)30464-5. [Epub ahead of print]12 274-284
    MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content.
    Elisa Balboa, Juan Castro, María-José Pinochet, Gonzalo I Cancino, Nuria Matías, Pablo José Sáez, Alexis Martínez, Alejandra R Álvarez, Carmen Garcia-Ruiz, José C Fernandez-Checa, Silvana Zanlungo.
      MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down-regulation of MLN64 in Niemann-Pick C1 deficient cells decreased mitochondrial cholesterol content, suggesting that MLN64 functions independently of NPC1. However, the role of MLN64 in the maintenance of endosomal cholesterol flow and intracellular cholesterol homeostasis remains unclear. We have previously described that hepatic MLN64 overexpression increases liver cholesterol content and induces liver damage. Here, we studied the function of MLN64 in normal and NPC1-deficient cells and we evaluated whether MLN64 overexpressing cells exhibit alterations in mitochondrial function. We used recombinant-adenovirus-mediated MLN64 gene transfer to overexpress MLN64 in mouse liver and hepatic cells; and RNA interference to down-regulate MLN64 in NPC1-deficient cells. In MLN64-overexpressing cells, we found increased mitochondrial cholesterol content and decreased glutathione (GSH) levels and ATPase activity. Furthermore, we found decreased mitochondrial membrane potential and mitochondrial fragmentation and increased mitochondrial superoxide levels in MLN64-overexpressing cells and in NPC1-deficient cells. Consequently, MLN64 expression was increased in NPC1-deficient cells and reduction of its expression restore mitochondrial membrane potential and mitochondrial superoxide levels. Our findings suggest that MLN64 overexpression induces an increase in mitochondrial cholesterol content and consequently a decrease in mitochondrial GSH content leading to mitochondrial dysfunction. In addition, we demonstrate that MLN64 expression is increased in NPC cells and plays a key role in cholesterol transport into the mitochondria.
    DOI:  https://doi.org/10.1016/j.redox.2017.02.024
  5. Blood. 2017 Mar 10. pii: blood-2016-10-741207. [Epub ahead of print]
    Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML.
    Sanduni U Liyanage, Rose Hurren, Veronique Voisin, Gaëlle Bridon, Xiaoming Wang, ChangJiang Xu, Neil MacLean, Thirushi P Siriwardena, Marcela Gronda, Dana Yehudai, Shrivani Sriskanthadevan, Daina Avizonis, Aisha Shamas-Din, Mark D Minden, Gary D Bader, Rebecca Laposa, Aaron D Schimmer.
      Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human AML samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared to normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared to normal hematopoietic samples. Knockdown of cytoplasmic nucleoside kinases reduced mtDNA levels in AML cells, demonstrating their contribution in maintaining mtDNA. To assess cytoplasmic nucleoside kinase pathway activity, we employed a nucleoside analog 2'3'-dideoxycytidine (ddC), which is phosphorylated to the activated anti-metabolite, 2'3'-dideoxycytidine triphosphate (ddCTP) by cytoplasmic nucleoside kinases. ddC is a selective inhibitor of the mitochondrial DNA polymerase, POLG. ddC was preferentially activated in AML cells compared to normal hematopoietic progenitor cells. ddC treatment inhibited mtDNA replication, oxidative phosphorylation, and induced cytotoxicity in a panel of AML cell lines. Furthermore, ddC preferentially inhibited mtDNA replication in a subset of primary human leukemia cells and selectively targeted leukemia cells while sparing normal progenitors cells. In animal models of human AML, treatment with ddC decreased mtDNA, electron transport chain proteins, and induced tumor regression without toxicity. ddC also targeted leukemic stem cells in secondary AML xenotransplantation assays. Thus, AML cells have increased cytidine nucleoside kinase activity that regulates mtDNA biogenesis and can be leveraged to selectively target oxidative phosphorylation in AML.
    DOI:  https://doi.org/10.1182/blood-2016-10-741207
  6. Sci Rep. 2017 Dec;7(1): 177
    Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression.
    Monique G P van der Wijst, Amanda Y van Tilburg, Marcel H J Ruiters, Marianne G Rots.
      Like the nucleus, mitochondria contain their own DNA and recent reports provide accumulating evidence that also the mitochondrial DNA (mtDNA) is subjective to DNA methylation. This evidence includes the demonstration of mitochondria-localised DNA methyltransferases and demethylases, and the detection of mtDNA methylation as well as hydroxymethylation. Importantly, differential mtDNA methylation has been linked to aging and diseases, including cancer and diabetes. However, functionality of mtDNA methylation has not been demonstrated. Therefore, we targeted DNA methylating enzymes (modifying cytosine in the CpG or GpC context) to the mtDNA. Unexpectedly, mtDNA gene expression remained unchanged upon induction of CpG mtDNA methylation, whereas induction of C-methylation in the GpC context decreased mtDNA gene expression. Intriguingly, in the latter case, the three mtDNA promoters were differentially affected in each cell line, while cellular function seemed undisturbed. In conclusion, this is the first study which directly addresses the potential functionality of mtDNA methylation. Giving the important role of mitochondria in health and disease, unravelling the impact of mtDNA methylation adds to our understanding of the role of mitochondria in physiological and pathophysiological processes.
    DOI:  https://doi.org/10.1038/s41598-017-00263-z
  7. J Biol Chem. 2017 Mar 10. pii: jbc.M117.776468. [Epub ahead of print]
    The Novel Chloroplast Outer Membrane Kinase KOC1 Is a Required Component of the Plastid Protein Import Machinery.
    Mónica Zufferey, Cyrille Montandon, Véronique Douet, Emilie Demarsy, Birgit Agne, Sacha Baginsky, Felix Kessler.
      The biogenesis and maintenance of cell organelles such as mitochondria and chloroplasts requires the import of many proteins from the cytosol, a process that is controlled by phosphorylation. In the case of chloroplasts, the import of hundreds of different proteins depends on Translocons at the Outer and Inner Chloroplast membrane (TOC and TIC, respectively) complexes. The essential protein TOC159 functions thereby as an import receptor. It has an N-terminal acidic (A) domain that extends into the cytosol, controls receptor specificity, and is highly phosphorylated in vivo. However, kinases that phosphorylate the TOC159 A-domain to enable protein import have remained elusive. Here, using co-purification with TOC159 from Arabidopsis, we discovered a novel component of the chloroplast import machinery, the regulatory Kinase of the Outer Chloroplast membrane 1 (KOC1). We found that KOC1 is an integral membrane protein facing the cytosol and stably associates with TOC. Moreover, KOC1 phosphorylated the A-domain of TOC159 in vitro, and in mutant koc1 chloroplasts, pre-protein import efficiency was diminished. koc1 Arabidopsis seedlings had reduced survival rates after transfer from the dark to the light in which protein import into plastids is required to rapidly complete chloroplast biogenesis. In summary, our data indicate that KOC1 is a functional component of the TOC machinery that phosphorylates import receptors, supports pre-protein import, and contributes to efficient chloroplast biogenesis.
    Keywords:  Arabidopsis; TOC complex; chloroplast; integral membrane kinase; phosphorylation; protein import; receptor
    DOI:  https://doi.org/10.1074/jbc.M117.776468
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