Are those 13 proteins really unimportable?

Mutations of the mitochondrial DNA, whether spontaneous in somatic cells or inherited, are now known to be at least partly responsible for a wide range of pathologies, ranging from very rare disorders such as Leigh's syndrome [1] through to very common ones such as Alzheimer's [2] and including aging itself. A conceptually simple treatment of these pathologies is to complement the mutant mtDNA with engineered copies of the 13 mt-coded proteins, which would reside chromosomally and be far less vulnerable to mutation [3]. Disparity of genetic codes and requirement for a targeting presequence are easily surmountable with current technology. However, the great hydrophobicity of these proteins seriously hinders their import; even yeast ATPase 9 proved non-trivial [4]. This has discouraged a systematic attempt to create functional transgenic copies of the human genes, despite promising results from a very simple presequence design strategy [5]. But such pessimism may be premature, given the recent discoveries that some of these genes are nuclear-coded in some plant species (which lack our main barrier to gene transfer, the disparity of genetic codes) [6]. Detailed study of those genes' presequences and/or chaperones may provide the clues necessary to engineer nuclear copies of their human homologues.

[1] Santorelli et al., 1993, Ann Neurol 34: 827-834
[2] Davis et al., 1997, Proc Natl Acad Sci USA 94: 4526-4531
[3] Lander and Lodish, 1990, Cell 61: 925-926
[4] Farrell et al., 1988, Eur J Biochem 173: 131-137
[5] Galanis et al., 1991, FEBS Lett. 282: 425-430
[6] Brennicke et al., 1993, FEBS Lett. 325: 140-145