The genetics of mitochondrial dysfunction
Mitochondria are the cell's power station, where the majority of energy is produced. These organelles contain their own DNA to encode the enzymes required for energy production. However, nuclear DNA is also involved in the biogenesis of mitochondria but the precise role of each genome in the process is largely unknown. Understanding the complex nature of the mitochondrial biogenesis process could provide essential mechanistic information regarding mitochondrial metabolic diseases. These multi-system disorders can affect up to 1 individual in 5 000 and are usually fatal. With this in mind, the EU-funded 'Biogenesis of the mitochondrial respiratory chain in children with severe multiorgan disorders' project aimed to identify key genes implicated in mitochondria biogenesis. To this end, researchers sequenced the coding regions of genes from a cohort of Finnish patients with respiratory chain deficiency syndrome. Exome sequencing sequencing has led to the identification of three additional very strong candidate genes including the MTFMT gene. Mutations in this gene affect the synthesis of the mitochondrial methionyl-tRNA formyl transferase enzyme. Lack of or overexpression of this protein synthesis initiator leads to a dysfunctional respiratory chain, suggesting that MTFMT expression is tightly regulated for physiological function. Further work indicated that MTFMT has a role in the assembly of mitochondrial respiratory chain and not in protein synthesis initiation as originally envisaged. The results of this study provided invaluable insight into the mechanisms underlying mitochondrial biogenesis. Importantly the BIOMIT study has identified new targets for genetic analysis of patients with respiratory chain deficiency which could be utilised for genetic counselling.
