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Structure and function of mitochondria and peroxisomes

Structure and function of mitochondria and peroxisomes. Láng, Orsolya MD, PhD Dept . Genetics , Cell & Immunobiology , Semmelweis University. www.dgci.sote.hu. Lecture EPh 2015. Endosymbiotic t heory – Similar Origin. Similarities : origin biogenesis

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Structure and function of mitochondria and peroxisomes

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  1. Structure and function of mitochondria and peroxisomes Láng, Orsolya MD, PhD Dept. Genetics, Cell & Immunobiology, Semmelweis University www.dgci.sote.hu LectureEPh2015

  2. Endosymbiotictheory – SimilarOrigin • Similarities: • origin • biogenesis • metabolicactivity: beta-oxidation

  3. ByConfocal M Mitochondrion By TEM By SEM

  4. History 1894 - Richard Altmannestablished them as cell organelles and called them "bioblasts" 1898 - The term "mitochondria" was coined by Carl Benda 1900 - Leonor Michaelisdiscovered Janus Greencan be used as a supravital stain for mitochondria 1913 particles from extracts of guinea-pig liver were linked to respiration by Otto Heinrich Warburg, which he called "grana". 1948 - Albert LesterLehningerdescribedtheoxidativephosphorylation 1952- The first „officialportrait” wastaken byhigh resolution micrographs 1957 - The popular term "powerhouse of the cell" was coined by Philip Siekevitz

  5. Mitochondrion Size Width 0.2-3.0 m length 7-10 m, butdynamically changeable

  6. Innermembrane of Mch crista tubular fingerprint-like berry-like

  7. Localisation Striatedductcells Spermcell

  8. Number of mitochondria Number/cell RBC, anaerobe cells of parasites – 0 Constant Spermcell – 24 Dynamicallychangeable Leukocytes ~300 Hepatocytes ~2000 Increasednumberinhyperthyroidpatients Chaos-Chaos ameba - 500.000 !

  9. Fission and fusion Drp1(outer and innermembranefission). Fis1 ( worksas receptor of Drp1) Mitofusinprotein (outermembranefusion), OPA1 (innermembranefusion), • Drp1-dynamin-related protein 1, Drp1 • Fis1 - Mitochondrialfission 1 protein • Opa1 - OpticAtrophy 1

  10. Dynamicmitochondria

  11. Composition I.compartmentalisation • Outermembrane • poorinproteins • characteristic protein: porin • (b-sheet– trimersformchannels) • permeabilityupto5000 dalton • fattyacids, triptophane and adrenalinemetabolizingenzymesarealsolocalizedintheoutermembrane

  12. OutermembraneproteinsinMitochondria and theirfunction channel translocators apoptosis fission Whatdoyouknowabout Tom40 ?

  13. OM- Porin • Big flow of moleculesacrossthemembrane • Porin protein: transmembraneprotein; • known from outer membranes of bacteria, mitochondria, and chloroplasts • Characterisedby number of antiparallel β-strands and by the shear number • 3 porinsforms a chanel; <5000 Da can go through • biggermoleculesaretransportedwithactivetransportacrossthemitochondrialtransporters

  14. Composition II. • Innermembrane • Increasedsurface • 70% proteins: • e- - transporterchaini • ATP synthesis • transporters • otherpointimpermeable – • 20% cardiolipin

  15. Proteins involved in oxidative phosphorylation http://www.bio.davidson.edu/genomics/2004/Wilson/yeast%20protein.htm

  16. ATP synthase – molecular motor Matrix/IC Stator: a,b,d Enchorethestructure F1 ATP-ase chatalytic site Rotor: Ɛ Spin clockwisewhen H+ enter IMS / EC Transmembrane proton carrierssubunit https://www.youtube.com/watch?v=GM9buhWJjlA

  17. H+ in ATP synthesis ATP cleavage H+ out Terms of Chemiosmotictheory Peter Dennis Mitchell • Mch. Respiratorychain – moveselectrons - pumps H+intointermembranespace • Mch. ATP synthaseworksalsoas a H+ pump. • Reversiblemechanism: • Severalcarriermoleculesformetabolites, ions – intheinnermembrane of Mch. • Otherpoint of theinnermembraneofMch. is impermeablefor H+ and OH-.

  18. Composition III. • Matrix • Pyruvatedehydrogenasecomplex • Enzymes of citricacidcycle • Enzymes of ß-oxydationoffattyacids • Enzymes of aminoacidoxydation • 5-10 copies of mtDNA (circular) • Enzymes of mtDNAreplication and transcription • Ribosomes (70S) • ATP, ADP, Pi • Mg2+, Ca2+, K+

  19. Function of Mitochondria • ATP synthesis • Regulation of Ca2+ levels in the cell (cationgranula) • Lipid homeostasis (lipid oxidation, steroid synthesis) • Nucleotide metabolism • Aminoacid metabolism • FE-S synthesis (Hem) • Ubiquinone synthesis • Cofactor synthesis • Apoptosis • Aging • Heat production

  20. Cellularrespiration

  21. ATP synthesis Upon one mol glucose oxidation, 36 mol ATPs are formedineukaryotes cytosol mitochondrium

  22. Szent-Györgyi – Kreb’scycle Formation of Acetyl-CoA

  23. Oxidativephosphorylation

  24. Oxygenabsent – NAD regenerationbyfermentation

  25. Heatproduction-thermogenesis Itis activated whenever the organism is in need of extra heat: febrile state- centrally controlled via hypothalamus feeding- low in proteindiet, leptin-dependent hypothalamic control Thermogenin= uncoupling protein 1 (UCP1)

  26. The human mitochondrial genome MT-DNA is circular, double-stranded structures consists of 16’569 base pairs carrying the information for 37 genes. http://www.mun.ca/biology/desmid/brian/BIOL2060/BIOL2060-18/18_25.jpg

  27. mt-DNA • ring shape, 5 –10 copies/Mch. • 13 Mtgenesarecodingproteins • thereare no introns • few regulator genes • no histons • replication, transcription, translation • 22 tRNA, 2 rRNA • Differencein protein synthesis: • 70S ribobome • protein synthesisstarts w/ fMet • antibioticsensitivity

  28. Semiautonomous organelle • growth and proliferation of mitochondria are controlled by both nuclear genome and it’s own genome. 98 % Apx. 1000 proteinsare distributed between the outer membrane, intermembrane space, inner membrane and matrix space

  29. Selectivetransport of proteinstoOrganells

  30. Major membranecomponents SAM complex TOM complex TIM 23 complex OXA complex TIM 22 complex

  31. Direct import of unfolded protein intomatrix 2 4 1 3

  32. Furtherrequirements • Chaperons – bothcytosolic and mitochondrial HSP70 • IM Membranepotential • Energy- ATP hydrolysis

  33. Integration of unfolded protein into OM • Beta - signalin C terminus • Chaperonsbidstothe protein in IMS • SAM complexesinsertthe protein inOM Whatkind of protein can be insertedin OM?

  34. Integration of protein into IM I. • N-terminus signalsequence • Hydrophobicsequence • TIM23 stopstranslocation • N-terminus signalsequence • Hydrophobicsequence – 2nd signal • OXA complexfoldsit • Mitochondrialproteinsaswell • Nameone protein!

  35. Integration of protein into IM II. • Metabolitetransportershaveinternalsignalsequence – loopin TOM • Chaperonsin IMS • TIM22 is specializedforinsertion of multipass IM proteins

  36. Whichpathwaycan be usedfor IMS proteins ?

  37. http://www.biochemie.uni-freiburg.de/ag/pfanner/research

  38. https://www.qiagen.com/geneglobe/static/images/pathways/mitochondrial%20protein%20import%20pathways.jpghttps://www.qiagen.com/geneglobe/static/images/pathways/mitochondrial%20protein%20import%20pathways.jpg

  39. Mathernalinheritance 2015. February U.K. Parliament approves controversial three-parent mitochondrial gene therapy

  40. Mutationrate of mtDNAbasedfamilyTree • weekrepairmechanism • - highmutationrate 100 timesfasterthaninthenucleus in 1980s Allan Wilson tested the mtDNA of 137 people from different parts of the world. Everyone alive today came from a single woman who lived in Africa about 200,000 years ago: Mitochondrial Eve. https://abagond.wordpress.com/2010/01/08/mitochondrial-dna/

  41. Mitochondrialdisorders and dysfunctions ! Secondray ! ! Primaryevents !

  42. Mitochondrialdisorders can be caused by mutations: in mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial components. Can be acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes Most sensitivecellsare: Neurons Muscellcells http://www.icmr.nic.in/ijmr/2015/janaury/0103.pdf

  43. http://www.icmr.nic.in/ijmr/2015/janaury/0103.pdf

  44. Inheritedmitochondrialdisorders • Nuclear DNA – mt-proteins • Congenital muscular dystrophy • Mt-DNA • Leber's Hereditary Optic • Neuropathy (Complex I) Both eyesareaffected Reason: nervusopticus (opticalnerve) and retina cellsdyebecause Mechanism : cause defects in several NADH-ubiquinoneoxidoreductase chains, therefore impair glutamate transport and increase reactive oxygen specieslevel Mitochondriawithparacrystalline

  45. Pharmacologicalaspects of Mtch • Strategies for mitochondrial pharmacology: • to make molecules selectively accumulate within mitochondria. • to use molecules that bind targets within mitochondria • to modulate processes outside mitochondria that ultimately alter mitochondrial function http://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147%2812%2900042-9

  46. Proofs of bacterialorigin 1. CircularmtDNA (Non-Mendelian inheritence) Animalmt: smallestgeneticsystemknown Translation of 13 polypeptide 2. Size of mitoribosomes (70 S) 3. Formylmethionineinitiatoraminoacid 4. Antibiotic sensitivity 5.Presence of porininGramnegativebacteria 6. Similarities of theelectrontransportchain and ATP synthase 7. Division of mitochondria

  47. Peroxisome ByConfocal M By TEM By SEM

  48. Structure • 0,3-1,5 µm • singlemembraneboundorganelle • Oxidativeenzymes : • Catalase • Ureateoxidasecrystalloid – notin human • Selective import • No genome - NoTranscription, Notranslation

  49. Composition I. • Peroxisomalmembraneproteins (PMP): • - peroxins (genes: PEX) • otherPMP e.g. „half „ ABC transporters)

  50. Composition II. Peroxisomalmatrix: Enzymes of oxidativeprocesses: Superoxiddismutase, catalase, peroxidase, Enzymes of metabolicpathways: fattyacidoxidation, bileacidsynthesis, enzymes of purin metabolism

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