Imported RNA in mammalian mitochondria

Abstract

The ‘division of genetic labour’ between nuclear and mitochondrial DNA (mtDNA) in mitochondrial protein synthesis in animal cells is controversial. As far as is known, all mitochondrial tRNAs, plus the two major rRNAs, are encoded by mtDNA, whereas all of the proteins involved in mitochondrial gene expression are nuclear encoded. In plants, fungi and protists, there are many examples of imported (nuclear-encoded) tRNAs, but compelling evidence for RNAimport into mammalian mitochondria has been lacking – until now.One recently documented example is the 5S rRNA, a proportion of which is found inside mitochondria 1xEvidence for the presence of 5S rRNA in mammalian mitochondria. Magalhaes, P.J et al. Mol. Biol. Cell. 1998; 9: 2375Crossref | PubMedSee all References1, although its function there is unknown. Other putatively imported RNAs have long been suggested to have roles in mitochondrial RNA processing. A particularly curious example concerns RNase P, the ribozyme involved in tRNA 5′ end maturation, which is apparently conserved from bacteria to man. No distinct mitochondrial RNase P has been characterized, and no gene for the catalytically essential RNA component of the enzyme can be found in mammalian mtDNA, although it is clearly present in yeast mtDNA. This leaves us with two alternatives: either mitochondrial pre-tRNA 5′ processing uses the same enzyme as in the nucleus, or a distinct enzyme inside mitochondria is entirely protein based. Preliminary reports in the literature unfortunately seemed to favour both options!The controversy has probably been laid to rest by Puranam and Attardi 2xThe RNase P associated with HeLa cell mitochondria contains an essential RNA component identical in sequence to that of the nuclear RNase P. Puranam, R.S and Attardi, G. Mol. Cell. Biol. 2001; 21: 548–561Crossref | PubMed | Scopus (82)See all References2, who report the characterization of an RNaseP in highly purified mitochondria that appears to be identical to the nuclear enzyme. Crucially, the enzyme is able in vitro to process correctly a mitochondrial pre-tRNA substrate, for Ser-tRNAUCN. The RNA component of the nuclear and mitochondrial enzymes is the same 340-nt H1 RNA species, encoded by a nuclear gene. Only a fraction of a percent of the total cellular H1 RNA content is recovered with the mitochondria, but it can be removed only by treatments that destroy organelle integrity. These findings raise the obvious questions of how H1 RNA (or intact RNase P holoenzyme, in a 17S particle also containing protein) enters mitochondria. The same authors also found tiny amounts of other small nuclear RNAs inside mitochondria, notably the RNA component of MRP, a ribozyme involved in nuclear pre-rRNA processing that was also originally proposed as a mitochondrial endoribonuclease.Clearly, if the biochemical pathways of mitochondrial RNA import in mammalian cells can be elucidated, a novel route will be established, whereby mitochondrial RNA can be manipulated, even if mtDNA transformation itself remains technically unfeasible. This could well offer a long-term prospect of gene therapy for correcting mitochondrial disorders involving tRNA gene mutations. At the very least, it would allow us to investigate more directly the molecular and physiological consequences of the presence inside mitochondria of mutant tRNAs.