The assembly of the human oxidative phosphorylation system.

Abstract

Mitochondria are the main energy producing organelles of the cell. Energy is produced by the oxidative phosphorylation (OXPHOS) system in the form of adenosine triphosphate (ATP). The complexes of the OXPHOS system are, except for complex II, encoded by mitochondrial (mt) as well as nuclear DNA (n). The nuclear and mitochondrial encoded subunits have to be assembled in the mitochondrial inner membrane in order to form a functional OXPHOS system. A few years ago most research has been focussed on the structural buildings blocks of the OXPHOS system in patients with a single enzyme deficiency. This has lead to the identification of many mutations in nuclear as well as mitochondrial encoded structural building blocks of the OXPHOS system. The fact that no mutations in the structural building blocks of complex IV have been detected is probably the main reason for a search to other nuclear encoded proteins involved in the functioning of the OXPHOS system. This has resulted in the discovery of many proteins involved in the assembly of the OXPHOS system complex IV. Mutations in these genes results in an enzymatic defect of only one of the OXPHOS system complexes, whereas many of the affected patients suffer from a deficiency involving more than one complex. In this thesis we address the question whether genes with a general role in mitochondrial functioning may be the cause of an OXPHOS system defect in patients with a combined deficiency of two or more OXPHOS system complexes. We have identified the underlying genetic cause of mitochondrial disorders in patients with a single deficiency of complex IV but also in a family with a combined deficiency of complex I, III and IV. The identification of these mutations is of utmost importance as we now can reliably offer prenatal diagnosis to the parents.