The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
98 The Mitochondrial Free Radical Theory of Aging Fig. 8.3. Cell division short-circuits the mechanism by pre-empting degradation. concentration falls; this again triggers mitochondrial replication. Finally, we can consider the case of the mutant mitochondrion: it can make some ATP and import more as needed, but will not have the same ATP concentration as a wild-type mitochondrion so engages in runaway (or at least accelerated) replication. This extremely neat model suffers, as noted above, only from rather inconclusive inconsistency with the evidence. The results of Chambers and Gingold 13 (see Section 8.3) are a direct refutation of preferential replication, but they have not been repeated in mammalian cells. Point mutations in ATPase subunits should be amplified by this mechanism just like other lesions, since the consequently greater proton gradient will cause faster membrane damage so trigger more frequent replication; but the evidence that such mutations do not accumulate is still restricted to only one report. 26 A third possible challenge derives from the segmental distribution of mutant mitochondria in muscle—the removal by lysosomes of supernumerary mitochondria in muscle fibers must be very assiduous, in order to prevent rapid propagation of a mutation along a fiber—but since we have no knowledge of this mechanism we cannot say that it is not so assiduous. A fourth is the report 8 that mitochondria undergo replication independent of the time since their previous division: this is incompatible with damage-driven replication because damage would be continuous, so mitochondrial generation time should be fairly uniform. This too is only weak evidence, though, because the experiment in question used dividing cells in culture, whereas a role for damage in mitochondrial replication is proposed only for non-dividing cells. Perhaps the best test would be to establish whether the replication of mitochondria in non-dividing
The Search for How Mutant mtDNA is Amplified cells is perinuclear, as SOS predicts, or occurs throughout the cell, as this model predicts; there is evidence that replication is perinuclear in vitro 9-11 but there is as yet no conclusive in vivo information on this point. References 1. Wallace DC. Mitochondrial DNA mutations and neuromuscular disease. Trends Genet 1989; 5:9-13. 2. Cortopassi GA, Arnheim N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 1990; 18:6927-6933. 3. Münscher C, Müller-Höcker J, Kadenbach B. Human aging is associated with various point mutations in tRNA genes of mitochondrial DNA. Biol Chem Hoppe Seyler 1993; 374:1099-1104. 4. Poulton J. Duplications of mitochondrial DNA: Implications for pathogenesis. J Inherit Metab Dis 1992; 15:487-498. 5. Edenberg HJ, Huberman JA. Eukaryotic chromosome replication. Annu Rev Genet 1975; 9:245-284. 6. Shoubridge EA, Karpati G, Hastings KE. Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease. Cell 1990; 62:43-49. 7. Wallace DC, Bohr VA, Cortopassi G et al. Group report: The role of bioenergetics and mitochondrial DNA mutations in aging and age-related diseases. In: Esser K, Martin GM, eds. Molecular Aspects of Aging. Chichester: John Wiley & Sons, 1995:199-225. 8. Bogenhagen D, Clayton DA. Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell 1977; 11:719-727. 9. Roussev R, Christov I, Stokrova J et al. A stable line of turkey bone marrow cells transformed by the myelocytomatosis virus strain MC31. Ultrastructural characteristics and localization of the DNA replication sites. Folia Biol 1992; 38:78-83. 10. Davis AF, Clayton DA. In situ localization of mitochondrial DNA replication in intact mammalian cells. J Cell Biol 1996; 135:883-893. 11. Schultz RA, Swoap SJ, McDaniel LD et al. Differential expression of mitochondrial DNA replication factors in mammalian tissues. J Biol Chem 1998; 273:3447-3451. 12. Ephrussi B, de Margarie-Hottinguer H, Roman H. Suppressiveness: A new factor in the genetic determinism of the synthesis of respiratory enzymes in yeast. Proc Natl Acad Sci USA 1956; 41:1065-1071. 13. Chambers P, Gingold E. A direct study of the relative synthesis of petite and grande mitochondrial DNA in zygotes from crosses involving suppressive petite mutants of Saccharomyces cerevisiae. Curr Genet 1986; 10:565-571. 14. Cortopassi GA, Shibata D, Soong NW et al. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 1992; 89:7370-7374. 15. Mitchell MB, Mitchell HK. A case of “maternal” inheritance in Neurospora crassa. Proc Natl Acad Sci USA 1952; 38:442-449. 16. Rizet G. Les modifications qui conduisent à la senescence chez Podospora: Sont-elles de nature cytoplasmique? C R Acad Sci Paris 1957; 244:663-666. 17. Muggleton A, Danielli JF. Inheritance of the “life-spanning” phenomenon in Amoeba proteus. Exp Cell Res 1967; 49:116-120. 18. Brand MD. The proton leak across the mitochondrial inner membrane. Biochim Biophys Acta 1990; 1018:128-133. 19. Rolfe DF, Brand MD. The physiological significance of mitochondrial proton leak in animal cells and tissues. Biosci Rep 1997; 17:9-16. 20. Skulachev VP. Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 1996; 29:169-202. 21. van Zutphen H, Cornwell DG. Some studies on lipid peroxidation in monomolecular and bimolecular lipid films. J Membr Biol 1973; 13:79-88. 99
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<strong>The</strong> Search for How Mutant mtDNA is Amplified<br />
cells is perinuclear, as SOS predicts, or occurs throughout the cell, as this model predicts;<br />
there is evidence that replication is perinuclear in vitro 9-11 but there is as yet no conclusive<br />
in vivo information on this point.<br />
References<br />
1. Wallace DC. <strong>Mitochondrial</strong> DNA mutations and neuromuscular disease. Trends Genet 1989;<br />
5:9-13.<br />
2. Cortopassi GA, Arnheim N. Detection <strong>of</strong> a specific mitochondrial DNA deletion in tissues<br />
<strong>of</strong> older humans. Nucleic Acids Res 1990; 18:6927-6933.<br />
3. Münscher C, Müller-Höcker J, Kadenbach B. Human aging is associated with various point<br />
mutations in tRNA genes <strong>of</strong> mitochondrial DNA. Biol Chem Hoppe Seyler 1993;<br />
374:1099-1104.<br />
4. Poulton J. Duplications <strong>of</strong> mitochondrial DNA: Implications for pathogenesis. J Inherit<br />
Metab Dis 1992; 15:487-498.<br />
5. Edenberg HJ, Huberman JA. Eukaryotic chromosome replication. Annu Rev Genet 1975;<br />
9:245-284.<br />
6. Shoubridge EA, Karpati G, Hastings KE. Deletion mutants are functionally dominant over<br />
wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease.<br />
Cell 1990; 62:43-49.<br />
7. Wallace DC, Bohr VA, Cortopassi G et al. Group report: <strong>The</strong> role <strong>of</strong> bioenergetics and<br />
mitochondrial DNA mutations in aging and age-related diseases. In: Esser K, Martin GM,<br />
eds. Molecular Aspects <strong>of</strong> <strong>Aging</strong>. Chichester: John Wiley & Sons, 1995:199-225.<br />
8. Bogenhagen D, Clayton DA. Mouse L cell mitochondrial DNA molecules are selected<br />
randomly for replication throughout the cell cycle. Cell 1977; 11:719-727.<br />
9. Roussev R, Christov I, Stokrova J et al. A stable line <strong>of</strong> turkey bone marrow cells transformed<br />
by the myelocytomatosis virus strain MC31. Ultrastructural characteristics and localization<br />
<strong>of</strong> the DNA replication sites. Folia Biol 1992; 38:78-83.<br />
10. Davis AF, Clayton DA. In situ localization <strong>of</strong> mitochondrial DNA replication in intact<br />
mammalian cells. J Cell Biol 1996; 135:883-893.<br />
11. Schultz RA, Swoap SJ, McDaniel LD et al. Differential expression <strong>of</strong> mitochondrial DNA<br />
replication factors in mammalian tissues. J Biol Chem 1998; 273:3447-3451.<br />
12. Ephrussi B, de Margarie-Hottinguer H, Roman H. Suppressiveness: A new factor in the<br />
genetic determinism <strong>of</strong> the synthesis <strong>of</strong> respiratory enzymes in yeast. Proc Natl Acad Sci<br />
USA 1956; 41:1065-1071.<br />
13. Chambers P, Gingold E. A direct study <strong>of</strong> the relative synthesis <strong>of</strong> petite and grande<br />
mitochondrial DNA in zygotes from crosses involving suppressive petite mutants <strong>of</strong><br />
Saccharomyces cerevisiae. Curr Genet 1986; 10:565-571.<br />
14. Cortopassi GA, Shibata D, Soong NW et al. A pattern <strong>of</strong> accumulation <strong>of</strong> a somatic deletion<br />
<strong>of</strong> mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 1992; 89:7370-7374.<br />
15. Mitchell MB, Mitchell HK. A case <strong>of</strong> “maternal” inheritance in Neurospora crassa. Proc<br />
Natl Acad Sci USA 1952; 38:442-449.<br />
16. Rizet G. Les modifications qui conduisent à la senescence chez Podospora: Sont-elles de<br />
nature cytoplasmique? C R Acad Sci Paris 1957; 244:663-666.<br />
17. Muggleton A, Danielli JF. Inheritance <strong>of</strong> the “life-spanning” phenomenon in Amoeba proteus.<br />
Exp Cell Res 1967; 49:116-120.<br />
18. Brand MD. <strong>The</strong> proton leak across the mitochondrial inner membrane. Biochim Biophys<br />
Acta 1990; 1018:128-133.<br />
19. Rolfe DF, Brand MD. <strong>The</strong> physiological significance <strong>of</strong> mitochondrial proton leak in animal<br />
cells and tissues. Biosci Rep 1997; 17:9-16.<br />
20. Skulachev VP. Role <strong>of</strong> uncoupled and non-coupled oxidations in maintenance <strong>of</strong> safely<br />
low levels <strong>of</strong> oxygen and its one-electron reductants. Q Rev Biophys 1996; 29:169-202.<br />
21. van Zutphen H, Cornwell DG. Some studies on lipid peroxidation in monomolecular and<br />
bimolecular lipid films. J Membr Biol 1973; 13:79-88.<br />
99