MtDNA mutations associated with sideroblastic anaemia cause a defect of mitochondrial cytochrome c oxidase.

We have recently described heteroplasmic mutations of mitochondrial DNA in patients suffering from sideroblastic anaemia. The mutations change conserved residues 1280 and M273 in subunit I of cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain. As a step towards elucidating the pathogenic mechanism, we studied the biochemical consequences of the mutations by transferring mtDNA from these patients' platelets into a permanent human cell line lacking a mitochondrial genome. Mutation-induced changes of the enzyme and the energy metabolism of the cells were characterised in the transmitochondrial cell lines. One of the mutations resulted in a decreased cellular concentration of the enzyme and a corresponding decrease in activity. The second mutation changed the structure around the binuclear centre and forced the cells to rely more strongly on glycolysis.