Mitochondrial-like tRNAs as splicing regulators

In Eukarya, including humans, protein-coding genes commonly consist of so-called exon sequences, which are translated into proteins and intervening intron sequences, which have to be excised from pre-messenger RNAs (mRNAs) prior to translation. Within intronic sequences from several nuclear encoded pre-mRNAs we have identified mitochondrial-like tRNA (mtl-tRNA) genes exhibiting an evolutionary conserved canonical tRNA structure. In this application, we want to investigate which roles these mtRNA genes are playing, located within introns of nuclear protein-coding genes. We postulate a model, in which mtRNAs exert a function in of pre-mRNA splicing. This model would reveal a novel gene regulatory mechanism, which identifies mitochondrial tRNAs as splicing regulators of nuclear encoded pre-mRNAs.

Our research, which was awarded the Prize of the State Capital of Innsbruck, demonstrated, for the first time, a biological function of mitochondrial DNA sequences, specifically mitochondrial tRNA genes, in the human nuclear genome. Mitochondria, as the centers of energy production in the cell, are essential components of human cells. However, they originally evolved from autonomous bacteria that symbiotically invaded the ancestors of human cells during evolution. As a result, like modern bacteria, they also possess their own DNA, i.e. their own so-called genome. Over the course of further evolution, parts of the mitochondrial genome were transferred into the nuclear genome; yet mitochondria still retain their own, original bacterial genome. Until now, it was unknown what function these sequences, which were transferred from the mitochondria to the nucleus, have, or whether they even have any function at all. Most human genes encoded in the nuclear genome consist of so-called coding exons and non-coding intron regions. During the process of splicing, the introns are removed, and the exons are joined together, with strict regulation over the order in which exons are connected. This results in specific new combinations of exon sequences, which are then translated into proteins, with specific functions. This can be imagined like a jigsaw puzzle, where certain combinations of exon sequences lead to different functions of the resulting protein. Interestingly, gene sequences originally derived from mitochondria, specifically mitochondrial transfer RNAs, are found in intronic regions of nuclear genes, which we have referred to as nimtRNAs. We were able to show that these nimtRNAs regulate how nuclear exon sequences are combined in the jigsaw puzzle-like manner and thus generate different proteins with various functions. With this discovery, my research group has, for the very first time, identified a function of these originally bacterial gene sequences in the human nuclear genome. The study, published in the highly prestigious journal Genome Biology, also shows that human genomes are constantly undergoing changes and are not static, remaining identical over millions of years. Furthermore, it highlights that in genome evolution, genes are often not completely "re-invented" but rather existing genes (e.g., mitochondrial tRNA genes) are repurposed and can be transformed into new functions, as we have now described for the first time with the mitochondrial nimtRNAs.