Newswise — GRACILE syndrome is a mitochondrial disease that is commonly found in Finland. It causes changes in cell metabolism and proliferation that are similar to cancer cells. However, a new study led by researchers at the Folkhälsan Research Center and the University of Helsinki has shown that limiting excessive cell proliferation could potentially treat mitochondrial diseases like GRACILE syndrome. This discovery could be a significant step forward in treating these conditions. The study was published in Nature Communications in April 2023.
Mitochondria are important for providing energy to cells in the body. When genes responsible for mitochondrial function are mutated, it can cause mitochondrial diseases in humans. GRACILE syndrome is one such mitochondrial disease that affects people with Finnish heritage. It is caused by a malfunction in the respiratory chain, which is how the mitochondria generate energy for cells. The disease starts in the fetal period and becomes apparent after birth as liver and kidney disease with metabolic complications. Infants born with the syndrome usually survive for only a few weeks.
Kallijärvi’s research group used a mouse model to show that in the tissues affected by GRACILE syndrome, cells experience a significant accumulation of DNA damage. This damage is caused by the cells attempting to grow and divide without sufficient energy, which leads to a failure in the cell division cycle. Ultimately, the tissues end up resembling premature ageing.
Understanding the disease mechanism helps to develop therapies
Cell growth and replication of DNA require a lot of energy and resources, which can make rapidly dividing cells more vulnerable to mitochondrial dysfunction. In organisms with multiple cells, protective mechanisms have evolved to ensure that cell division occurs properly and to prevent cancer. However, in mice with the GRACILE syndrome mutation, some of these protective mechanisms failed, and their tissues developed DNA damage, which made them resemble premature ageing. The researchers discovered that the expression of the cancer gene c-MYC increased significantly in the affected tissues of the mice. They also found that inhibiting the function of c-MYC in the liver cells of the mice with a specially designed miniprotein reduced the DNA damage.
According to Kallijärvi, the most remarkable finding in their study was the significant increase in a protein called c-MYC, which stimulates cell growth. The excessive c-MYC protein seemed to drive the cells to replicate even when they lacked sufficient energy and resources, leading to a detrimental cycle of events.
Researchers prevented effects of ageing in mice
The researchers were surprised to find evidence of illicit cell proliferation underlying premature ageing in their experiments. They used a mitochondrial enzyme, alternative oxidase (AOX), as a gene therapy to compensate for the dysfunction in the respiratory chain. They found that AOX did not improve the main functions of the respiratory chain as expected, but it did suppress mitochondrial stress signaling and the excessive cell proliferation that caused the ageing changes. This discovery suggests that limiting excessive cell proliferation could potentially be a treatment for mitochondrial diseases such as GRACILE syndrome.
The researchers found that a ketogenic diet, which they had previously shown to improve the liver disease in the mice with GRACILE syndrome, had a similar effect on the cell cycle and DNA damage. Ketogenic diets have also been tested as a treatment for patients with less severe 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.
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