Respiratory complex I in brain development and genetic disease.

A study is presented on the expression and activity of complex I, as well as of other complexes of the respiratory chain, in the course of brain development and inherited encephalopathies. Investigations on mouse hippocampal cells show that differentiation of these cells both in vivo and in cell cultures is associated with the expression of a functional complex I, whose activity markedly increases with respect to that of complexes III and IV. Data are presented on genetic defects of complex I in six children with inborn encephalopathy associated with isolated deficiency of the complex. Mutations have been identified in nuclear and mitochondrial genes coding for subunits of the complex. Different mutations were found in the nuclear NDUFS4 gene coding for the 18 kD (IP, AQDQ) subunit of complex I. All the NDUFS4 mutations resulted in impairment of the assembly of a functional complex. The observations presented provide evidence showing a critical role of complex I in differentiation and functional activity of brain cells.