Classification of mitochondrial diseases

A single classification of mitochondrial diseases does not exist because of the uncertainty of the contribution of nuclear genome mutations to their etiology and pathogenesis. Existing classifications are based on 2 principles: the participation of a mutant protein in oxidative phosphorylation reactions and whether the mutant protein is encoded by mitochondrial or nuclear DNA.

Based on the duality of the coding of mitochondrial proteins in the processes of tissue respiration and oxidative phosphorylation (nuclear and purely mitochondrial), the etiological principle distinguishes 3 groups of hereditary diseases.

• Mitochondrial diseases due to gene mutations of nuclear DNA:
  • defects in transport substrates;
  • defects in recycling substrates;
  • defects of the enzymes of the Krebs cycle;
  • disturbance of oxidative phosphorylation;
  • disturbances in the respiratory chain; about defects in the import of proteins.
• Mitochondrial diseases, which are based on mutations of mitochondrial DNA:
  • sporadic mutations;
  • point mutations of structural genes;
  • point mutations of synthetic genes.
• Mitochondrial diseases associated with violation of intergenomic signal effects:
  • multiple deletions of mitochondrial DNA, but inherited by autosomal dominant type;
  • deletion (decrease in the number) of mitochondrial DNA, inherited by autosomal recessive type.

There are also acquired mitochondrial diseases associated with exposure to toxins, drugs, and aging.

To date, the pathogenesis of mitochondrial diseases has been well studied. In the form of a scheme it can be presented in stages in the following way: transport of substrates, their oxidation, Krebs cycle, the functioning of the respiratory chain, conjugation of tissue respiration and oxidative phosphorylation. Transport of substrates is carried out with the help of special transport proteins - translocase, which transfer dicarboxylic acids, ATP, ADP, calcium ions, glutamate, etc. The basic substrates of mitochondria are pyruvate and fatty acids, the transport of which provides carnitine-palmitoyl transferase and carnitine.

Oxidation of substrates occurs with the participation of enzymes pyruvate dehydrogenase complex, consisting of 3 enzymes: pyruvate dehydrogenase, lipoate acetyltransferase and lipoamide dehydrogenase with the formation of acetyl-CoA, which is included in the Krebs cycle. The utilization of fatty acids occurs step by step in the process of beta oxidation. In the course of these reactions, the resulting electrons are transferred to the respiratory chain of the mitochondria. The complete decomposition of pyruvate occurs in the Krebs cycle, which results in the formation of NAD and FAD molecules, which transmit their electrons to the respiratory chain. The latter is formed by 5 multi-enzyme complexes, 4 of which carry electron transport, and the fifth catalyzes the synthesis of ATP. The complex of the respiratory chain is under the dual control of the nuclear and mitochondrial genomes.

From the perspective of pathogenesis, there are 3 main groups of mitochondrial diseases.

• Diseases of oxidative phosphorylation processes.
• Diseases of beta-oxidation of fatty acids.
• Defects in the metabolism of pyruvate and the Krebs cycle.

From the point of view of the leading biochemical defect mitochondrial diseases are divided into the following groups.

• Transport substrate defects.
  • Deficiency of monocarboxylic translocase.
  • Disturbance of carnitine-acylcarnitine transport (primary carnitine insufficiency, carnitine system insufficiency, mixed forms of carnitine deficiency, secondary carnitine insufficiency, deficiency of carnithalmitoyltransferase 1 and 2, combined carnitine and carnitine-palmitoyltransferase deficiency).
• Defects in the utilization of substrates.
  • Defects of oxidation of pyruvate:
    • insufficiency of pyruvate decarboxylase;
    • insufficiency of dihydrolipoyltransetylase;
    • insufficiency of dihydrolipoyldehydrogenase;
    • insufficiency of pyruvate dehydrogenase;
    • insufficiency of pyruvate carboxylase;
    • deficiency of carnitine-acetyltransferase.
• Defects in the metabolism of free fatty acids: defects in beta-oxidation of fatty acids.
• Defects in the respiratory chain.
  • Defects of NADH: KoQ-reductase complex (with normal carnitine and carnitine insufficiency).
  • Defects of KoQ cytochrome b, cl-reductase complex (KoQ-10 insufficiency, insufficiency of Fe-S proteins, cytochrome b deficiency, combined deficiency of cytochromes b and cl).
  • Insufficiency of cytochrome a, a3.
  • Insufficiency of cytochrome a, a3 and b.
• Defects in the accumulation and transmission of energy.
  • Disturbances of oxidative phosphorylation with hypermetabolism (Luft's disease).
  • Disorders of oxidative phosphorylation without hypermetabolism.
  • Lack of mitochondrial ATPase.
  • Insufficient adenine nucleotide translocase.

Currently, the classification is based on the etiological principle, with the allocation in each group of several subgroups of diseases. It is most reasonable.

[1], [2], [3], [4], [5], [6], [7]