Presentation is loading. Please wait.

Presentation is loading. Please wait.

Berkeley Feb 2004 Outer membraneInter-membrane spaceInner membraneMatrixCristae.

Similar presentations


Presentation on theme: "Berkeley Feb 2004 Outer membraneInter-membrane spaceInner membraneMatrixCristae."— Presentation transcript:

1

2 Berkeley Feb 2004

3 Outer membraneInter-membrane spaceInner membraneMatrixCristae

4

5 ATP ADP + Pi H+H+ H+H+ ATP hydrolysis

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

7 Electrons enter the respiratory chain at a redox potential of–300mV Ubiquinone pool at 0mV Cytochrome c at +250mV H 2 O at +800mV Complex I Complex II Complex III Complex IV ATP synthase

8 Proton extrusion generates large membrane potential  (~150mV) and small pH gradient  pH (~0.5pH units) +150mV, -0.5  pH Total driving force for protons = protonmotive force  p =  pH

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

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

11 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

12  m Matrix Ca 2+ ATP generation Reactive oxygen species NADP + REDUCTION Glutathione reduction Respiratory chain

13 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)

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

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

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

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

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

19 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

20 I II III IV Q Rotenone Malonate Some specific mitochondrial inhibitors

21 Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 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: (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

22 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: 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.

23 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: 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.

24 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. Ca 2+ overload of mitochondria and activation of the permeability transition

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

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

27 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

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

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

30 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

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

32 O 2.- H2O2H2O2 Superoxide dismutases; SOD1, CuZn, cytoplasmic SOD2, Mn, mitochondrial matrix SOD Glutathione peroxidase H2OH2O GSH GSSG NADPH NADP + NADH NAD + Glutathione reductase transhydrogenase NO ONOO -

33 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

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

35 Table 9.1 some mitochondrial mutations location Pearson's syndrome, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia (CPEO) ‘Common deletion’ of 4977 base pairs between A8 and ND5. All mt protein synthesis abolished due to lack of tRNAs MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). tRNA leu(UUR) All mt protein synthesis abolished due to lack of tRNAs MERRF (myoclonus, epilepsy, with ragged-red fibers) tRNA lys All mt protein synthesis abolished due to lack of tRNAs Leber’s hereditary optic neuropathy (LHON), 6 point mutations in Complex I ND genes loss of Complex I activity NARP (neuropathy, ataxia and retinitis pigmentosa). A6Inhibition of ATP synthase

36 Schapira AHV (1998) Mitochondrial dysfunction in neurodegenerative disorders. Biochim Biophys Acta Bio- Energetics 1366: 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.

37 Paperback: 288 pages Publisher: Academic Press; ISBN: ; $49.95

38


Download ppt "Berkeley Feb 2004 Outer membraneInter-membrane spaceInner membraneMatrixCristae."

Similar presentations


Ads by Google