Mechanism resembling ageing and cancer found in a Finnish mitochondrial disease

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, a member of the Finnish disease heritage, is caused by a malfunction in complex III of the respiratory chain, the very system the mitochondria utilize to generate cellular energy. The onset of the syndrome is already in the fetal period, manifesting as a liver and kidney disease with severe metabolic complications. Newborn infants with the syndrome usually die by a few weeks of age.

Our study found that mouse model of GRACILE syndrome, carrying the same mutation as the patients, shows cancer-like changes in proliferating cells, causing tissues to age prematurely. The finding is a significant step forward in understanding the syndrome and developing treatments for mitochondrial diseases.

We demonstrated that in the key tissues affected by the syndrome, such as the liver, cells accumulate DNA damage. The damage arises from the cells trying to grow and divide against lack of energy and other resources like nucleotides needed for DNA and RNA. Consequently, they fail the cell division cycle, eventually drifting into a state resembling ageing. In the whole animal, this process results in a disease known as progeria, which means a premature ageing disease.

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 mechanisms do not work in the mice with complex III dysfunction. We 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 viral gene therapy decreased the DNA damage. Interestingly, ketogenic diet had a similar effect.

Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria
Purhonen J, Banerjee R, Wanne V, Sipari N, Mörgelin M, Fellman V, Kallijärvi J. Nature Communications.