Molecular characteristics

Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in children, accounting for approximately 30 percent of cases. FOXRED1 encodes a protein that may act as a chaperone protein required for the function of mitochondrial complex I. Mutations in this gene are associated with mitochondrial complex I deficiency.

FOXRED1 has been proposed to be a dual function protein: an assembly factor for mitochondrial complex I biogenesis and a key enzyme of amino acid metabolism. As a member of the D-amino acid oxidases, FOXRED1 is functional as an oxidoreductase, and it is hypothed that this protein can participate in glycine metabolism which in turn modulates glutathione biosynthesis, an antioxidant protecting the cells from reactive oxygen species (ROS). Complex I is the major entry point for electrons into the respiratory chain and also a major producer of ROS species. Mitochondrial disorders are often conditions of oxidative stress and symptoms can arise as a result of a functional deficiency that has an assembly factor, reducing complex I activity with a significant increase on ROS species, and on the other hand, as a result of metabolic activity deficiency leading to glutathione depletion and preventing the correct cellular ROS detoxification.

It could be that depending on the mutation location in FOXRED1, the impact on the quaternary structure of the protein and therefore, in its loss of function, can affect complex I assembly and/or metabolic activity of the ROS species, in different forms influencing the clinical severity spectrum of these disorders.