Premature aging in tissues is caused by a mitochondrial disease in newborns, which exhibits cancer-like changes in rapidly multiplying cells, according to a recent study. The research sheds light on GRACILE syndrome, one of the Finnish heritage diseases, and may aid in the development of treatments for other mitochondrial diseases in the future.
The syndrome, which causes liver and kidney disease and severe metabolic complications, is the result of a malfunction in the respiratory chain, the system used by mitochondria to generate cellular energy. Newborns with the disease have a low survival rate of just a few weeks.
The study, conducted at the Folkhälsan Research Center and the University of Helsinki, was led by docent Jukka Kallijärvi and professor emerita Vineta Fellman and published in Nature Communications in April 2023. The mitochondria, responsible for a large portion of cellular energy metabolism, cause mitochondrial diseases in humans when mutations occur in the genes required for their function. The research team used a mouse model to demonstrate that the affected tissues accumulate significant DNA damage when they attempt to grow and divide despite a lack of energy. As a result, they fail in the cell division cycle, and the tissues eventually become akin to premature aging.
Understanding the disease mechanism helps to develop therapies
The energy and resources required for cell growth and genome replication make rapidly dividing cells highly vulnerable to mitochondrial dysfunction. In multicellular organisms, there are stringent mechanisms in place to protect the cell division process, such as cancer prevention. However, in mice with the GRACILE syndrome mutation, some of these safeguards were found to be ineffective.
The research team discovered that the expression of the cancer gene c-MYC had increased by up to 40 times in the affected tissues. Inhibiting the function of c-MYC in the liver cells of the mutant mice using a miniprotein designed as a cancer drug reduced DNA damage.
The most remarkable finding in the study, according to Kallijärvi, was that an increase in a protein that promotes cell growth appeared to force the cells to continue dividing despite limited resources, resulting in a damaging cycle. The findings demonstrate the critical role of c-MYC in the pathogenesis of GRACILE syndrome and may have implications for the development of targeted therapies for mitochondrial diseases.
Researchers prevented effects of aging in mice
The discovery that illicit cell proliferation contributes to premature aging was a surprising outcome of experiments in which a mitochondrial enzyme alternative oxidase (AOX) was expressed as a form of gene therapy to compensate for respiratory chain dysfunction. AOX did not improve any of the primary functions of the respiratory chain, but it did significantly reduce mitochondrial stress signaling and curtail excessive cell proliferation, thereby preventing aging-related changes.
Interestingly, a ketogenic diet, previously found to improve liver disease in these mice, produced similar effects on the cell cycle and DNA damage. Ketogenic diets have been tested as a treatment for patients with less severe mitochondrial diseases.
The researchers are now investigating the mechanisms that trigger mitochondrial stress signaling and whether mitigating harmful cell proliferation would relieve the disease in the mouse model.
Source: University of Helsinki