GRACILE syndrome, a mitochondrial disease that is part of the Finnish disease heritage, shows altered cell metabolism and proliferation resembling that of cancer cells. In future, similar mitochondrial diseases could potentially be treated by limiting excessive cell proliferation, which would be a significant progress. This is demonstrated in a study led by docent Jukka Kallijärvi and professor emerita Vineta Fellman. The study, carried out at the Folkhälsan Research Center and the University of Helsinki, was published in Nature Communications in April 2023.
Mitochondria are organelles responsible for a large part of cellular energy metabolism. Mutations in genes required for mitochondrial functions cause mitochondrial diseases in humans. GRACILE syndrome is caused by a malfunction in the respiratory chain, the very system the mitochondria utilize to generate cellular energy. The onset of the syndrome is already in the foetal period, manifesting after birth as a liver and kidney disease with severe metabolic complications. Newborn infants with the syndrome survive usually only a few weeks.
Using a mouse model, Kallijärvi’s research group demonstrated that in the key tissues affected by the syndrome cells accumulate massive DNA damage. The damage arises from the cells trying to grow and divide against lack of energy. Consequently, they fail the cell division cycle, and the tissues eventually drift into a state resembling premature ageing.
Understanding the disease mechanism helps to develop therapies
Cell growth and replication of the genome consumes a lot of energy and building blocks, potentially making proliferating cells particularly susceptible to mitochondrial dysfunction. In multicellular organisms, evolution has developed strict mechanisms to safeguard the cell division process, for example as protection against cancer. However, some of these did not work in the mice carrying the GRACILE syndrome mutation. The research group found that the expression of the cancer gene c-MYC had increased as much as 40-fold in the sick tissues. Inhibiting the function of c-MYC in the liver cells of the mutant mice with a miniprotein designed as a cancer drug reduced the DNA damage.
“This was the most astounding discovery in our study. A dramatic increase in a protein that promotes cell growth appears to force the cells to proliferate despite inadequate resources, resulting in a harmful vicious circle” Kallijärvi says.
Researchers prevented effects of ageing in mice
Convincing evidence on illicit cell proliferation underlying the premature ageing came as a surprise in experiments where the researchers expressed a mitochondrial enzyme alternative oxidase as a kind of gene therapy to compensate the dysfunction in the respiratory chain. Unexpectedly, AOX did not improve any of the main functions of the respiratory chain. Still, it almost completely suppressed mitochondrial stress signalling as well as the excessive cell proliferation, preventing the ageing changes.
Interestingly, a ketogenic diet, which the researchers earlier found to improve the liver disease in these mice, had a similar effect on the cell cycle and DNA damage. Ketogenic diets have been trialled as a treatment in patients with milder mitochondrial diseases.
The researchers are now looking into what mechanisms triggered the mitochondrial stress signalling and whether blunting the harmful cell proliferation would alleviate the disease in the mouse model.
