Reversible Infantile Liver Failure

The Study of RILF Through a Genetically Modified Murine Mouse Model

While studying RILF (reversible infantile liver failure), a mitochondrial disease that can cause severe unbalance in liver functions during infancy, scientists in Japan have found that they can explore the mechanisms involved with the progress of the condition through the use of a new murine model. The model is designed to show how MTU1 – a vital mitochondrial enzyme – plays a major role in influencing the development of the liver in its early stages, as well as impacting embryonic development as a whole.

The Unique Effects of MTU1 on the Regulation of Protein Translation

As soon as they started using knockout mice as part of their experiments, the scientists noticed immediately that MTU1 has a strong impact on the mouse embryo’s development. Their main focus was to explore and study the effects that the enzyme had on the regulation of mitochondrial protein translation. For that purpose, they have come up with several lines of knockout mice:

  • Wild-type Mtu1 +/+ mice and Heterozygous Mtu1 +/- mice, which developed normally without any visible negative effecets;

  • And the Homozygous Mtu1 -/- mouse models, which showed some startling results, failing to develop further than a week past insemination.

The discovery prompted the Japanese researchers to acknowledge the importance of the MTU1 enzyme, and their line of research has led to the use of gene elimination in order to come up with a liver-specific knockout mouse – the MtuiLKO model. Although in this model the visibly adverse developmental effects associated with the homozygous mice were not present, clear signs of liver damage were found. These were consistent with the symptoms of RILF patients, and also included symptoms such as mitochondrial morphological differences, the lack of sulfur-containing modifications in three mt-tRNAs and various metabolic modifications. Additionally, a lower level of protein translation seemed to indicate that Mtu1 plays a key role in the process.

What Do the Results Suggest?

The results of the experiments conducted by Professor Kazuhito Tomizawa of Kumamoto University – the leader of the project – and his team seem to piece together the puzzle in determining why the effects of RILF are as unique as they seem to appear from patient logs associated with both mild and severe cases of the condition, and why some patients can actually recover from it without any further problems. Like in RILF patients, fibroblast growth factor 21 increased as mitochondrial function decreased, and a powerful antioxidant response was also present in MtuLKO mice. These were the clues necessary for the researchers at Kumamoto University to establish why the mice were still in good condition after 16 weeks and some even began recovering as they grew older.

The unique traits of the murine model used as part of the experiments conducted by the Japanese scientists seem to be the main reason why similar studies did not yield the same results – as other types of animal models were used as part of those studies – however, they also clearly indicate that Professor Tomizawa and his team may be able to find a viable treatment for RILF with its help.