When cellular energy production goes wrong
The OXPHOS process is carried out in specialised cellular organelles, known as mitochondria, and disturbances in the enzyme complexes, DNA maintenance or protein synthesis can lead to mitochondrial OXPHOS disorders. These are often fatal, causing multi-system damage mainly of organs and tissues with a high energy demand. Studying the clinical and pathophysiological consequences of OXPHOS diseases was the subject of the EU-funded ‘Rational treatment strategies combating mitochondrial oxidative phosphorylation (OXPHOS) disorders’ (Eumitocombat) project. Among the project’s aims was to identify genes involved in the formation and regulation of the OXPHOS process and develop efficient screening methods for studying the components of energy metabolism. Work on normal and disease mitochondria added substantial new information on the enzymes required for mitochondrial DNA maintenance and transcription. Valuable data were also obtained on defects of the nucleotide metabolism that cause mitochondrial DNA depletion syndrome. By creating a knockout mouse model of a negative regulator of mitochondrial transcription, scientists were able to identify new factors involved in the OXPHOS enzyme complex. A combination of genetic, bioinformatic and biochemical methods helped to further delineate the role of such complexes in normal mitochondria biogenesis. The Eumitocombat project provided novel insight into the role of mitochondrial DNA maintenance as a cause of OXPHOS-related diseases. Project results have the capacity to be implemented into clinical practice, reinforcing Europe as the international leader in the development of treatments for combating these disorders.
