1 / 37

Berkeley Feb 2004

Berkeley Feb 2004. Outer membrane. Inter-membrane space. Inner membrane. Matrix. Cristae. ATP hydrolysis. ADP + Pi. H +. H +. ATP. ++. --. The proton circuit: Continuous generation of ATP. ADP + Pi. H +. H +. ATP. Energy (redox energy, photons etc). Cytochrome c at +250mV.

aphrodite-harrington
Download Presentation

Berkeley Feb 2004

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Berkeley Feb 2004

  2. Outer membrane Inter-membrane space Inner membrane Matrix Cristae

  3. ATP hydrolysis ADP + Pi H+ H+ ATP

  4. ++ -- The proton circuit: Continuous generation of ATP ADP + Pi H+ H+ ATP Energy (redox energy, photons etc)

  5. Cytochrome c at +250mV Ubiquinone pool at 0mV H2O at +800mV Electrons enter the respiratory chain at a redox potential of–300mV Complex IV Complex I Complex II Complex III ATP synthase

  6. Proton extrusion generates large membrane potential Dy (~150mV) and small pH gradient DpH (~0.5pH units) +150mV, -0.5DpH Total driving force for protons = protonmotive force Dp = Dy - 60 DpH

  7. Mitochondria work like an electrical circuit. • The 'battery' is the respiratory chain Electrical circuit Mitochondrion Proton current Electron current + + Voltage 1.5V Voltage 0.2V Mitochondrial membrane _ _

  8. The respiratory chain has 3 proton pumps in parallel with respect to the proton circuit Mitochondrion Proton current + Voltage 0.2V III I IV Mitochondrial membrane _

  9. The proton circuit is governed by Ohm’s law: Current = voltage/resistance roughly: Respiration rate = constant x membrane potential / resistance to proton re-entry* *through ATP synthase or leakage across membrane

  10. Glutathione reduction NADP+ REDUCTION ATP generation Dym Respiratory chain Reactive oxygen species Matrix Ca 2+

  11. Mitochondria and ‘stress’ i.e. under which circumstances might the Mitochondria’s ability to maintain a high ATP/ADP ratio and a reducing environment fail? A. Oxygen limitation (stroke, heart attack, near drowning)

  12. GLUTAMATE COMPARTMENTATION cytoplasm 10mM synaptic vesicles 100mM synaptic cleft 1:M 'Classic EM images from the lab of John Heuser (Washington University)'

  13. GLUTAMATE EXCITOTOXICITY 1. (BIOENERGETIC DEFICIT RESULTING FROM OXYGEN DEPROIVATION CAUSES ATP COLLAPSE, FAILURE OF PLASMA MEMBRANE SODIUM PUMPS AND MASSIVE GLUTAMATE RELEASE) 'Classic EM images from the lab of John Heuser (Washington University)'

  14. GLUTAMATE EXCITOTOXICITY 2. POST-SYNAPTIC NMDA RECEPTORS PATHOLOGICALLY ACTIVATED 'Classic EM images from the lab of John Heuser (Washington University)'

  15. GLUTAMATE EXCITOTOXICITY 3. MASSIVE Ca 2+ ENTRY AND ACCUMULATION BY MITOCHONDRIA 'Classic EM images from the lab of John Heuser (Washington University)'

  16. GLUTAMATE EXCITOTOXICITY 4. MITOCHONDRIAL Ca 2+ LOADING CAN INITIATE DELAYED CELL DEATH M M 'Classic EM images from the lab of John Heuser (Washington University)'

  17. Mitochondria and ‘stress’ i.e. under which circumstances might the Mitochondria’s ability to maintain a high ATP/ADP ratio and a reducing environment fail? B. Respiratory chain restriction

  18. Rotenone Malonate Some specific mitochondrial inhibitors I III Q IV II

  19. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979-980. Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPP+). it is proposed that this chemical selectively damages cells in the substantia nigra Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36: 2503-2508. (MPP+), a major metabolite of the neurotoxin, (MPTP) inhibited the oxidation of NADH-linked substrates by brain mitochondrial preparations. Compromise of mitochondrial oxidative capacity by MPP+ could be an important factor in mechanisms underlying the toxicity of MPTP

  20. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3: 1301-1306. chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

  21. Beal MF, Brouillet E, Jenkins B, Henshaw R, Rosen B, Hyman BT (1993) Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. J Neurochem 61: 1147-1150. Abstract: Intrastriatal injection of malonate, a reversible inhibitor of succinate dehydrogenase (SDH), produced age dependent striatal lesions… The results strengthen the possibility that a subtle impairment of energy metabolism may play a role in the pathogenesis of Huntington's disease.

  22. Mitochondria and ‘stress’ i.e. under which circumstances might the Mitochondria’s ability to maintain a high ATP/ADP ratio and a reducing environment fail? C. Ca2+ overload of mitochondria and activation of the permeability transition

  23. ) e Permeability transition M mitochondria e r m f ( l a n i r o i d t n a r o t h n c e o c t i n m o - c 'set-point' a r + t a 2 x 2+ 2+ 2+ C Ca Ca Ca e Ca 2+

  24. Permeability transition leads to matrix swelling, unfolding of inner membrane, bursting of outer membrane and release of cytochrome c

  25. Mitochondria and ‘stress’ i.e. under which circumstances might the Mitochondria’s ability to maintain a high ATP/ADP ratio and a reducing environment fail? D. Mitochondria and pro-apoptotic stress

  26. Death receptor Plasma Membrane Activation of downstream effector caspases Procaspase-8 Caspase-8 e.g. caspase-3 t-Bid Bid Caspase-9 Apaf-1 Bax + C Procaspase-9 (+) (-) Bcl-2 * Bax Outer Mitochondrial Membrane Putative BAx/Bid channel C Inner Q Mitochondrial Membrane 9-05

  27. Apoptosis Necrosis Ca 2+ Apoptotic signal Reactive Oxygen Species Cytochrome c Caspase activation Cell Death Cell Death

  28. Mitochondria and ‘stress’ i.e. under which circumstances might the Mitochondria’s ability to maintain a high ATP/ADP ratio and a reducing environment fail? E. Mitochondria and oxidative stress

  29. Reactive oxygen species (ROS): superoxide anion produced by complexes I and III (increased at high membrane potential) O2 + e- = O2.- cf: O2 + 4e- + 4H+ = 2H2O superoxide superoxide

  30. Superoxide dismutases; SOD1, CuZn, cytoplasmic SOD2, Mn, mitochondrial matrix Glutathione peroxidase SOD O2.- H2O2 H2O GSH GSSG NO Glutathione reductase ONOO- NADPH NADP+ transhydrogenase NADH NAD+

  31. Mitochondria and ‘stress’ i.e. under which circumstances might the mitochondria’s ability to maintain a high ATP/ADP ratio and a reducing environment fail? F. Defects in the mitochondrial genome

  32. 1 2 O (origin) s H r b R t y N c y A v a e n i H a h c 1 6 s t r h R g N n i A L i a 6 h D c N 5 C D N 4 8 A 4 9 4 5 1 4 N 4 1 O H N M E L L O A S N H D 3 2 1 L 4 3 G L H O N 3 4 6 0 A L H O N 1 1 7 7 8 N A M A E 2 R D N R P R 8 F 9 N 9 D 4 O (origin) 8 3 3 L G 4 / 4 C G N D 4 L N I D X 3 O C C O X I n I o I i A t I A e I T l e X T P d P O a n o a s C m s e m e o 6 c 8 9-06

  33. Table 9.1 some mitochondrial mutations location Pearson's syndrome, Kearns-Sayre ‘Common deletion’ of All mt protein synthesis syndrome, chronic progressive 4977 base pairs abolished due to lack of tRNAs external ophthalmoplegia (CPEO) between A8 and ND5. leu(UUR) MELAS (mitochondrial tRNA encephalomyopathy, lactic acidosis All mt protein synthesis and stroke-like episodes). abolished due to lack of tRNAs lys MERRF (myoclonus, epilepsy, tRNA All mt protein synthesis with ragged-red fibers) abolished due to lack of tRNAs Leber’s hereditary optic 6 point mutations in loss of Complex I activity neuropathy (LHON), Complex I ND genes NARP (neuropathy, ataxia and A6 Inhibition of ATP synthase retinitis pigmentosa).

  34. Schapira AHV (1998) Mitochondrial dysfunction in neurodegenerative disorders. Biochim Biophys Acta Bio-Energetics 1366: 225-233 Mutations of mitochondrial DNA (mtDNA) are associated with a wide spectrum of disorders encompassing the myopathies, encephalopathies and cardiomyopathies, in addition to organ specific presentations such as diabetes mellitus and deafness. Parkinson's disease , Huntington's disease , Friedreich's ataxia. In any event, mitochondria present an important target for future strategies for 'neuroprotection' to prevent or retard neurodegeneration.

  35. Paperback: 288 pages • Publisher: Academic Press; ISBN: 0125181213; • $49.95

More Related