Classification of mitochondrial diseases

There is no unified classification of mitochondrial diseases due to the uncertainty of the contribution of nuclear genome mutations to their etiology and pathogenesis. Existing classifications are based on two principles: the participation of the mutant protein in oxidative phosphorylation reactions and whether the mutant protein is encoded by mitochondrial or nuclear DNA.

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

• Mitochondrial diseases caused by gene mutations of nuclear DNA:
  • defects of transport substrates;
  • defects of utilization substrates;
  • defects of Krebs cycle enzymes;
  • oxidative phosphorylation disorder;
  • disturbances in the respiratory chain; o defects in protein import.
• Mitochondrial diseases that are based on mutations in mitochondrial DNA:
  • sporadic mutations;
  • point mutations of structural genes;
  • point mutations of synthetic genes.
• Mitochondrial diseases associated with disruption of intergenomic signaling effects:
  • multiple deletions of mitochondrial DNA, but inherited in an autosomal dominant manner;
  • deletions (reduction in quantity) of mitochondrial DNA, inherited in an autosomal recessive manner.

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

By now, the pathogenesis of mitochondrial diseases has been studied quite well. In the form of a diagram, it can be presented step by step as follows: transport of substrates, their oxidation, the Krebs cycle, functioning of the respiratory chain, coupling of tissue respiration and oxidative phosphorylation. Substrate transport is carried out with the help of special transport proteins - translocases, which transfer dicarboxylic acids, ATP, ADP, calcium ions, glutamate, etc. The main substrates of mitochondria are pyruvate and fatty acids, the transport of which is provided by carnitine palmitoyl transferase and carnitine.

Oxidation of substrates occurs with the participation of enzymes of the 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. Utilization of fatty acids occurs in stages in the process of beta oxidation. During these reactions, the electrons formed are transferred to the respiratory chain of mitochondria. Complete decomposition of pyruvate occurs in the Krebs cycle, resulting in the formation of NAD and FAD molecules that transfer their electrons to the respiratory chain. The latter is formed by 5 multienzyme complexes, 4 of which transport electrons, and the fifth catalyzes the synthesis of ATP. The respiratory chain complex is under dual control of the nuclear and mitochondrial genomes.

From the standpoint of pathogenesis, 3 main groups of mitochondrial diseases can be distinguished.

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

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

• Defects in substrate transport.
  • Monocarboxytranslocase deficiency.
  • Disorders of carnitine-acylcarnitine transport (primary muscle carnitine deficiency, systemic carnitine deficiency, mixed forms of carnitine deficiency, secondary carnitine deficiency, carnitine palmitoyltransferase 1 and 2 deficiency, combined carnitine and carnitine palmitoyltransferase deficiency).
• Defects in substrate utilization.
  • Pyruvate oxidation defects:
    • pyruvate decarboxylase deficiency;
    • dihydrolipoyltransacetylase deficiency;
    • dihydrolipoyl dehydrogenase deficiency;
    • pyruvate dehydrogenase deficiency;
    • pyruvate carboxylase deficiency;
    • carnitine acetyltransferase deficiency.
• Defects in free fatty acid metabolism: defects in fatty acid beta-oxidation.
• Respiratory chain defects.
  • Defects of NADH:KoQ reductase complex (with normal carnitine levels and with carnitine deficiency).
  • Defects of KoQ cytochrome b, cl-reductase complex (KoQ-10 deficiency, Fe-S protein deficiency, cytochrome b deficiency, combined deficiency of cytochromes b and cl).
  • Cytochrome A, A3 deficiency.
  • Cytochrome a, a3 and b deficiency.
• Defects in energy storage and transmission.
  • Disorders of oxidative phosphorylation with hypermetabolism (Luft disease).
  • Disorders of oxidative phosphorylation without hypermetabolism.
  • Mitochondrial ATPase deficiency.
  • Adenine nucleotide translocase deficiency.

Currently, the classification adopted is based on the etiological principle, with several subgroups of diseases being identified in each group. It is the most justified.

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