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The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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A Challenge from Textbook Bioenergetics and <strong>Free</strong> <strong>Radical</strong> Chemistry<br />

to cross between surface and bulk, thus reducing the surface-to-surface proton-motive<br />

force (∂p) and impairing OXPHOS. It has indeed been shown 49 that the degree to which<br />

proton conduction is preferentially lateral varies with the density <strong>of</strong> negatively charged<br />

head groups.<br />

This idea is too new to have undergone the detailed analysis by the bioenergetics<br />

community that will be needed before it can be accepted as a valid refinement <strong>of</strong> the<br />

chemiosmotic theory. I anticipate that such scrutiny will be intensive, because the<br />

ramifications <strong>of</strong> this model for our understanding <strong>of</strong> mitochondrial function are very<br />

pr<strong>of</strong>ound. For example, one vital role <strong>of</strong> mitochondria in vivo is cellular calcium homeostasis:<br />

they are able to take up and store calcium when there is an excess <strong>of</strong> it in the cytosol, so<br />

stabilising its cytosolic concentration. <strong>The</strong> textbook model for how they achieve this relies<br />

on the presence <strong>of</strong> a large bulk-to-bulk Δψ, which causes cations (<strong>of</strong> which calcium in solution<br />

is <strong>of</strong> course one) to leak, slowly, through the mitochondrial membrane. If there is in fact no<br />

Δψ, that mechanism must be radically revised.<br />

Presuming that this model survives such scrutiny, however, it finally shows—after a<br />

whole chapter <strong>of</strong> twists and turns—that SOS is, after all, compatible with the rise in superoxide<br />

levels that is caused by certain types <strong>of</strong> respiratory chain inhibition.<br />

References<br />

1. Sastre J, Pallardo FV, Pla R et al. <strong>Aging</strong> <strong>of</strong> the liver: Age-associated mitochondrial damage<br />

in intact hepatocytes. Hepatology 1996; 24:1199-1205.<br />

2. a)Hagen TM, Yowe DL, Bartholomew JC et al. <strong>Mitochondrial</strong> decay in hepatocytes from<br />

old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad<br />

Sci USA 1997; 94:3064-3069.<br />

2. b)Bandy B, Davison AJ. <strong>Mitochondrial</strong> mutations may increase oxidative stress: implications<br />

for carcinogenesis and aging? <strong>Free</strong> Radic Biol Med 1990; 8:523-539.<br />

3. Mitchell P. Protonmotive redox mechanism <strong>of</strong> the cytochrome b-c1 complex in the<br />

respiratory chain: protonmotive ubiquinone cycle. FEBS Lett 1975; 56:1-6.<br />

4. Link TA. <strong>The</strong> role <strong>of</strong> the ‘Rieske’ iron sulfur protein in the hydroquinone oxidation (Q(P))<br />

site <strong>of</strong> the cytochrome bc1 complex. <strong>The</strong> ‘proton-gated affinity change’ mechanism. FEBS<br />

Lett 1997; 412:257-264.<br />

5. a)Brandt U. Proton-translocation by membrane-bound NADH: Ubiquinone-oxido-reductase<br />

(complex I) through redox-gated ligand conduction. Biochim Biophys Acta 1997;1318:79-91.<br />

5. b)Sen K, Beattie DS. Cytochrome b is necessary for the effective processing <strong>of</strong> core protein<br />

I and the iron-sulfur protein <strong>of</strong> complex III in the mitochondria. Arch Biochem Biophys<br />

1986; 251:239-249.<br />

5. c)Guidot DM, McCord JM, Wright RM et al. Absence <strong>of</strong> electron transport (Rho 0 state)<br />

restores growth <strong>of</strong> a manganese-superoxide dismutase- deficient Saccharomyces cerevisiae<br />

in hyperoxia. Evidence for electron transport as a major source <strong>of</strong> superoxide generation<br />

in vivo. J Biol Chem 1993; 268:26699-26703.<br />

5. d)Yoneda M, Katsumata K, Hayakawa M et al. Oxygen stress induces an apoptotic cell<br />

death associated with fragmentation <strong>of</strong> mitochondrial genome. Biochem Biophys Res<br />

Commun 1995; 209:723-729.<br />

5. e)Liang BC, Ullyatt E. Increased sensitivity to cis-diamminedichloroplatinum induced<br />

apoptosis with mitochondrial DNA depletion. Cell Death Differ 1998; 5:694-701.<br />

6. Horgan DJ, Singer TP, Casida JE. Studies on the respiratory chain-linked reduced<br />

nicotinamide adenine dinucleotide dehydrogenase. 13. Binding sites <strong>of</strong> rotenone, piericidin<br />

A, and amytal in the respiratory chain. J Biol Chem 1968; 243:834-843.<br />

7. Boveris A, Chance B. <strong>The</strong> mitochondrial generation <strong>of</strong> hydrogen peroxide. General<br />

properties and effect <strong>of</strong> hyperbaric oxygen. Biochem J 1973; 134:707-716.<br />

8. Boveris A, Cadenas E, Stoppani AO. Role <strong>of</strong> ubiquinone in the mitochondrial generation<br />

<strong>of</strong> hydrogen peroxide. Biochem J 1976; 156:435-444.<br />

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