Mitochondrial Disorders

Mendelian inheritance refers to the transmission of genes encoded by DNA contained in the nuclear chromosomes. In addition, each mitochondrion contains several copies of a small circular chromosome. The mitochondrial DNA (mtDNA) is ~16.5 kb and encodes transfer and ribosomal RNAs and 13 proteins that are components of the respiratory chain involved in oxidative phosphorylation and ATP generation.

The mitochondrial genome does not recombine and is inherited through the maternal line because sperm does not contribute significant cytoplasmic components to the zygote. A noncoding region of the mitochondrial chromosome, referred to as D-loop, is highly polymorphic. This property, together with the absence of mtDNA recombination, makes it a valuable tool for studies tracing human migration and evolution, and it is also used for specific forensic applications.

Inherited mitochondrial disorders are transmitted in a matrilineal fashion; all children from an affected mother will inherit the disease, but it will not be transmitted from an affected father to his children . Alterations in the mtDNA affecting enzymes required for oxidative phosphorylation lead to reduction of ATP supply, generation of free radicals, and induction of apoptosis.

 Several syndromic disorders arising from mutations in the mitochondrial genome are known in humans and they affect both protein-coding and tRNA genes . The broad clinical spectrum often involves (cardio)myopathies and encephalopathies because of the high dependence of these tissues on oxidative phosphorylation. The age of onset and the clinical course are highly variable because of the unusual mechanisms of mtDNA transmission, which replicates independently from nuclear DNA.

During cell replication, the proportion of wild-type and mutant mitochondria can drift among different cells and tissues. The resulting heterogeneity in the proportion of mitochondria with and without a mutation is referred to as heteroplasmia and underlies the phenotypic variability that is characteristic of mitochondrial diseases.

Selected Mitochondrial Diseases

1. MELAS syndrome: mitochondrial myopathy with encephalopathy, lactacidosis, and stroke

2. Leber's optic atrophy: hereditary optical neuropathy

3. Kearns-Sayre syndrome (KSS): ophthalmoplegia, pigmental degeneration of the retina, cardiomyopathy

4. MERRF syndrome: myoclonic epilepsy and ragged-red fibers

5. Neurogenic muscular weakness with ataxia and retinitis pigmentosa (NARP)

6. Progressive external ophthalmoplegia (CEOP)

7. Pearson syndrome (PEAR): bone marrow and pancreatic failure

8. Autosomal dominant inherited mitochondrial myopathy with mitochondrial deletion (ADMIMY)

9. Somatic mutations in cytochrome b gene: exercise intolerance, lactic acidosis, complex III deficiency, muscle pain, ragged-red fibers


Acquired somatic mutations in mitochondria are thought to be involved in several age-dependent degenerative disorders affecting predominantly muscle and the peripheral and central nervous system (e.g., Alzheimer's and Parkinson's disease). Establishing that a mtDNA alteration is causal for a clinical phenotype is challenging because of the high degree of polymorphism in mtDNA and the phenotypic variability characteristic of these disorders. Certain pharmacologic treatments may have an impact on mitochondria and/or their function. For example, treatment with the antiretroviral compound azidothymidine (AZT) causes an acquired mitochondrial myopathy through depletion of muscular mtDNA.