The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
Share Embed Flag
Download ePaper

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

pliki.supernova.com.pl
from pliki.supernova.com.pl More from this publisher
15.01.2013 Views

176 The Mitochondrial Free Radical Theory of Aging 7. Benoit PW, Belt WD. Destruction and regeneration of skeletal muscle after treatment with a local anaesthetic, bupivacaine (Marcaine). J Anat 1970; 107:547-556. 8. Carlson BM, Emerick S, Komorowski TE et al. Extraocular muscle regeneration in primates. Local anesthetic-induced lesions. Ophthalmology 1992; 99:582-589. 9. Clark KM, Bindoff LA, Lightowlers RN et al. Reversal of a mitochondrial DNA defect in human skeletal muscle. Nature Genet 1997; 16:222-224.

CHAPTER 15 Transgenic Copies of mtDNA: Techniques and Hurdles The conclusion of the previous chapter is somewhat ambivalent: I believe that selective ablation of affected cells is a concept worthy of consideration and research, but may in the end prove unable to retard systemic mtDNA decline all that much. Therefore, I feel that only one approach to subverting mtDNA decline is really likely to work well: complementation of mtDNA mutations with transgenic copies introduced into the chromosomal DNA. This approach has been discussed for some years, starting with the first demonstration of its feasibility in 19861 and with suggestions for its use in treating diseases2 and aging. 3 Consequently there are many aspects of it which merit detailed description here. The first nine sections of this chapter deal with potential obstacles to mitochondrial gene therapy by protein import; the first eight will be argued to be either spurious or currently hypothetical, and therefore not meriting concern at this point, but the ninth—the mt-coded proteins’ hydrophobicity—is acknowledged to be very real. The remaining sections of the chapter focus on ways to overcome or sidestep that obstacle. 15.1. Changes to the Coding Sequences A gene that is encoded in the mitochondrion is translated using mitochondrial tRNAs; a gene encoded in the nucleus is translated using cytoplasmic tRNAs. It was explained in Sections 2.4.4 and 10.2 that the amino acid sequence resulting from translation of a given nucleotide sequence will be different in the two cases—the genetic codes are different. Therefore, if we take a gene from the mtDNA and insert it into the nucleus, the protein resulting from its translation will almost certainly not work, because it will include numerous incorrect amino acids. Worse, it may be prematurely truncated by virtue of a codon that should mean an amino acid being, instead, seen as a “stop” codon; this will be the fate of UGA codons, as explained in Section 10.2. The way to avoid this difficulty is to change the DNA sequence, before inserting it into the nucleus, to mirror the differences of genetic code. That way, the correct amino acid sequence will result from cytoplasmic translation. Of course that will mean that the DNA would now generate the wrong sequence if it were translated in mitochondria; but we will not need intramitochondrial translation, so that is no problem. The introduction of base-pair changes in this way is well within the scope of existing molecular biology. In fact it was first achieved (in yeast) in 1986, 1 and a highly efficient technique for making multiple such changes simultaneously was developed more recently. 4 15.2. Targeting to Mitochondria It is not going to be any use, however, to restore to cells the ability to make their mt-coded proteins, if those proteins are not then incorporated into the mitochondrial OXPHOS The Mitochondrial Free Radical Theory of Aging, by Aubrey D.N.J. de Grey. ©1999 R.G. Landes Company.

176<br />

<strong>The</strong> <strong>Mitochondrial</strong> <strong>Free</strong> <strong>Radical</strong> <strong>The</strong>ory <strong>of</strong> <strong>Aging</strong><br />

7. Benoit PW, Belt WD. Destruction and regeneration <strong>of</strong> skeletal muscle after treatment with<br />

a local anaesthetic, bupivacaine (Marcaine). J Anat 1970; 107:547-556.<br />

8. Carlson BM, Emerick S, Komorowski TE et al. Extraocular muscle regeneration in primates.<br />

Local anesthetic-induced lesions. Ophthalmology 1992; 99:582-589.<br />

9. Clark KM, Bind<strong>of</strong>f LA, Lightowlers RN et al. Reversal <strong>of</strong> a mitochondrial DNA defect in<br />

human skeletal muscle. Nature Genet 1997; 16:222-224.

logo

products

Resources

Company

Terms of service
Privacy policy
Cookie policy
Cookie settings
Imprint
Change language
Made with love in Switzerland
© 2024 Yumpu.com all rights reserved

Hooray! Your file is uploaded and ready to be published.

Saved successfully!

Ooh no, something went wrong!