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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.

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slide2

Outer membrane

Inter-membrane space

Inner membrane

Matrix

Cristae

slide4

ATP hydrolysis

ADP + Pi

H+

H+

ATP

slide5

++

--

The proton circuit:

Continuous generation

of ATP

ADP + Pi

H+

H+

ATP

Energy (redox energy, photons etc)

slide6

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

slide7

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

slide8

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

_

_

slide9

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

_

slide10

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

slide11

Glutathione

reduction

NADP+

REDUCTION

ATP generation

Dym

Respiratory chain

Reactive

oxygen

species

Matrix Ca 2+

slide12

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)

slide13

GLUTAMATE COMPARTMENTATION

cytoplasm 10mM

synaptic vesicles 100mM

synaptic cleft 1:M

\'Classic EM images from the lab of John Heuser (Washington University)\'

slide14

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)\'

slide15

GLUTAMATE EXCITOTOXICITY

2. POST-SYNAPTIC NMDA RECEPTORS PATHOLOGICALLY ACTIVATED

\'Classic EM images from the lab of John Heuser (Washington University)\'

slide16

GLUTAMATE EXCITOTOXICITY

3. MASSIVE Ca 2+ ENTRY AND ACCUMULATION BY MITOCHONDRIA

\'Classic EM images from the lab of John Heuser (Washington University)\'

slide17

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)\'

slide18

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

slide19

Rotenone

Malonate

Some specific mitochondrial inhibitors

I

III

Q

IV

II

slide20

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

slide21

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.

slide22

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.

slide23

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

slide24

)

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+

slide25

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

slide26

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

slide27

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

slide28

Apoptosis

Necrosis

Ca 2+

Apoptotic

signal

Reactive Oxygen Species

Cytochrome c

Caspase activation

Cell Death

Cell Death

slide29

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

slide30

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

slide31

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+

slide32

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

slide33

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

slide34

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).

slide35

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.

slide36

Paperback: 288 pages

  • Publisher: Academic Press; ISBN: 0125181213;
  • $49.95
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