BIOMIT

Biogenesis of the mitochondrial respiratory chain in children with severe multiorgan disorders

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 Obiettivo del progetto (Objective)

'The final goal of the project is to better understand the mechanisms involved in mitochondrial disorders in children caused by the isolated or combined respiratory chain complex I deficiency. Mitochondrial disorders are the most frequent cause of inborn metabolic errors, affecting 1 individual in 5000. Symptoms begin at birth or in early childhood in most cases and generally present as multi-system disorders with a fatal outcome. The majority of the patients die within a few years of the first clinical manifestation. Currently, the genetic origin of the isolated or combined complex I deficiency can be resolved only in the minority of cases suggesting that mutations in yet-unknown factors are a very important cause of disease. At present, the biogenesis of the mitochondrial respiratory chain enzymes is far from understood. Recently, functional complementation and bioinformatic studies carried out in the laboratory of prof. Shoubridge (McGill University, the outgoing host) have led to the identification of two complex I assembly factors and a translational activator for a subunit of complex IV. In this study, in collaboration with prof. Shoubridge, new information on the pathogenesis of mitochondrial disorders is obtained by monitoring the cellular responses at the functional, translational and protein level in different conditions and species. Novel pathogenic mutations will be identified as the underlying genetic cause of the isolated or combined complex I defect in Finnish pediatric patients. In addition, systematic screening of respiratory chain deficient mutants and studies on mice and plants will lead to the discovery of novel factors that control the biogenesis of the mitochondrial respiratory chain. This study will be of significant impact on the medical field by providing new targets for genetic analysis of patients with respiratory chain deficiency. The results of this study can be utilized in the genetic counselling of the patients and their family.'

Introduzione (Teaser)

Metabolic breakdown of various substances in our body occurs in specialised organelles known as mitochondria. EU researchers investigated the genetic background of patients with mitochondrial dysfunction.

Descrizione progetto (Article)

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.