Definition and classification

Neurological syndromes are the most frequent clinical presentations of mitochondrial disorders, a group of human diseases characterized by defects of the mitochondrial energy output. Mitochondrial energy metabolism is composed of several pathways, including the pyruvate dehydrogenase complex, the Krebs’ cycle, the mitochondrial beta-oxidation of fatty acids, etc., along with specialized transport systems specific to adenosine triphosphate/ adenosine diphosphate (ATP/ADP), metabolites, substrates, etc. However, the term ‘mitochondrial disorders’ is, to a large extent, applied to the clinical syndromes associated with abnormalities of the common final pathway of the mitochondrial energy metabolism, i.e., the oxidative phosphorylation (OXPHOS). OXPHOS is carried out in the inner mitochondrial membrane by the five enzymatic complexes of the respiratory chain (Zeviani and Antozzi, 1997).

From a genetic standpoint, the respiratory chain is unique, because it is formed through the complementation of two separate genetic systems, the nuclear and the mitochondrial genomes. Nuclear genes provide most of the protein subunits of the respiratory complexes, the factors that control their intramitochondrial transport, assembly, and turnover, as well as the enzymes for the synthesis of prosthetic groups. In addition, most of the components of the mitochondrial DNA (mtDNA)-replication and mtDNA-expression systems are encoded by genes localized in the nucleus. In turn, human mtDNA, a maternally transmitted circular minichromosome, present in two to ten copies per organelle, is composed of mRNAgenes encoding 13 subunits of respiratory complexes I, III, IV, and V, as well as of tRNA-genes and rRNA-genes that are part of the RNA apparatus deputed to intra-organellar mtDNA translation (Anderson et al., 1981).