Pathogenesis and treatment of mitochondrial disorders

Abstract

In the past 50 years, our understanding of the biochemical and molecular causes of mitochondrial diseases, defined restrictively as disorders due to defects of the mitochondrial respiratory chain (RC), has made great strides. Mitochondrial diseases can be due to mutations in mitochondrial DNA (mtDNA) or in nuclear DNA (nDNA) and each group can be subdivided into more specific classes. Thus, mtDNA-related disorders can result from mutations in genes affecting protein synthesis in toto or mutations in protein-coding genes. Mendelian mitochondrial disorders can be attributed to mutations in genes that (i) encode subunits of the RC ("direct hits"); (ii) encode assembly proteins or RC complexes ("indirect hits"); (iii) encode factors needed for mtDNA maintenance, replication, or translation (intergenomic signaling); (iv) encode components of the mitochondrial protein import machinery; (v) control the synthesis and composition of mitochondrial membrane phospholipids; and (vi) encode proteins involved in mitochondrial dynamics.In contrast to this wealth of knowledge about etiology, our understanding of pathogenic mechanism is very limited. We discuss pathogenic factors that can influence clinical expression, especially ATP shortage and reactive oxygen radicals (ROS) excess. Therapeutic options are limited and fall into three modalities: (i) symptomatic interventions, which are palliative but crucial for day-to-day management; (ii) radical approaches aimed at correcting the biochemical or molecular error, which are interesting but still largely experimental; and (iii) pharmacological means of interfering with the pathogenic cascade of events (e.g. boosting ATP production or scavenging ROS), which are inconsistently and incompletely effective, but can be safe and helpful.

Fig. 10.1

Serial cross-sections of the muscle biopsy from a patient with KSS and a large-scale mtDNA deletion. A. With the modified Gomori trichrome, ragged-red fibers (RRF) show irregular crimsom staining; B. With the succinate dehydrogenase (SDH) stain, the same fibers appear dark blue (“ragged-blue” fibers); C. With the cytochrome c oxidase (COX) stain, most RRF lack COX activity either completely or partially; D. By superimposing the SDH and COX stains, normal fibers appear brown, while COX-deficient fibers stand out as blue (Courtesy of Drs. Eduardo Bonilla and Kurenai Tanji, Columbia University Medical Center)

Fig. 10.2

Scheme of the mitochondrion showing selected metabolic pathways. The spirals depict the reactions of the β-oxidation pathway, resulting in the liberation of acetyl-coenzyme A (CoA) and the reduction of flavoprotein. See the list of abbreviations at the end of the text

Fig. 10.3

Schematic view of human mtDNA, showing the gene products for the 12S and 16S ribosomal RNAs, the subunits of NADH-coenzyme Q oxidoreductase (ND), cytochrome c oxidase (COX), cytochrome b (cyt b), and ATP synthase (A), and 22 tRNAs (1-letter amino acid nomenclature), the origins of heavy- and light-strand replication (O_H and O_L) and the promoters of heavy- and Light-strand transcription (HSP and LSP). Some pathogenic mutations are indicated. The arc removed by the “common deletion” is subtended by the two radii. For abbreviations and acronyms, see the list at the end of the text. (Reproduced from the Annual Review of Neuroscience [39] with permission)

Fig. 10.4

The mitochondrial respiratory chain (RC), showing nDNA-encoded subunits in blue and mtDNA-encoded subunits in red. Coenzyme Q and cytochrome c are electron (e⁻) carriers. Diseases are listed according to the affected RC complex and divided in defects of RC subunits and defects of assembly proteins

Fig. 10.5

Cross-sections of human muscle stained for COX. A, normal; B. patient with LS due to mutations in SURF1; C. patient with encephalocardiomyopathy due to mutations in SCO2