Introduction

Clinical symptoms of mitochondrial disorders

Mitochondria, the “power stations of the cell”, are essential organelles which supply the vast majority of cellular energy demands. To achieve this they use a system of membrane-bound enzymes, the respiratory chain enzymes. The mitochondrial respiratory chain consists of five multienzyme complexes (complex I-V) and two small coenzymes, coenzyme Q10 and cytochrome C. The oxidation of substrates in the respiratory chain is linked to ATP production and is also called oxidative phosphorylation (OXPHOS).

Mitochondrial diseases are caused by a disturbed function of the respiratory chain which may be due to abnormalities of nuclear or mitochondrial encoded proteins.

Typical signs of mitochondrial disorders are:

• Maternal inheritance (paternal mitochondria are degraded in the zygote), but spontaneous new mutations in a person are also commonly seen
• Multiorgan involvement with predilection of organs with high energy demands (CNS, muscle, kidneys, cochlea, liver)
• Extremely high phenotypic variability, even within the same family
• Primary manifestation is possible at any age
• Tissue-specific expression of the defect is common with mtDNA mutations

Clinically, a number of mitochondrial disorders show a “classical phenotype” (MELAS , MERRF , CPEO , LHON ) which – if present – permits direct molecular genetic verification of the disesase without prior biochemical testing. For those patients, however, who do not fit a “classical phenotype” the first step should be the biochemical analysis of the respiratory chain enzyme activities in muscle and/or fibroblasts. Having established a mitochondrial respiratory chain defect, further molecular genetic testing is then possible. Because of the close interactions between respiratory chain and other metabolic pathways (tricyclic acid cycle, fatty acid oxidation) abnormal intermediary metabolites (lactate, pyruvate, ketone bodies, TCA cycle intermediates) are frequently seen and may be regarded as indicators for an underlying respiratory chain defect.

Mitochondrial genetics

A particularly interesting feature of mitochondria is the dual genetic control of the respiratory chain enzymes by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Mitochondrial diseases are therefore classified into disorders caused by mtDNA mutations and disorders due to nDNA mutations.

Mutations of mtDNA are a well-known group of mitochondrial diseases with an estimated cumulative prevalence in the population of 1:5000. The mtDNA molecule is circular, double-stranded and consists of 16569 base pairs. It encodes for important subunits of complex I, III, IV, V, ribosomal RNAs and tRNAs; all other mitochondrial proteins are nuclear encoded. Since each mitochondrion contains several (up to 10) copies of mtDNA and each cell a huge number of mitochondria, many hundred or even thousand alleles of a mtDNA gene coexist in each cell – in contrast to nuclear genes with only two alleles per cell. A particular mtDNA mutation does not usually affect all mitochondrial alleles, but only a certain percentage of alleles with the consequence that two populations of mtDNA will co-exist in the affected cells – a wild-type one and a mutated one. This is called heteroplasmy. It is thought that about 10% wildtype DNA are sufficient to maintain mitochondrial function, but this threshold for the development of clinical disease is quite variable and tissue-specific.