Mitochondrial diseases
From Ganfyd
The characteristics of mitochondria with their key contributions to oxidative phosphorylation and cell apoptosis ensure a number of diseases due to toxins involve the mitochrondria. The existence of a separate 16.6 Kb long circular mtDNA to the rest of the human genome produces a number of genetic diseases that tend to be characterised by transmission through the maternal line and marked variation in phenotype (see review [1]). There are many other mitochondrial disorders considered in detail elsewhere.
Contents |
Toxin Induced Diseases
- Mitochondrial Complex I
- Mitochondrial Complex IV (13 polypeptides)-Four redox centres, 2 heme centres (a and a3) and 2 copper centres (CuA and CuB)
- Cyanide and azide form a bridge between Cytochrome a3 and CuB.
- Thiocyanate and formate bind to Cytochrome a3-CuB in subunit 1
- Dicyclohexylcarbodiimideinhibitor of proton transport at the binuclear center in subunit I.
Degenerative disease
Abnormalities in mitochondrial function or evidence of mitochondrial triggering of apoptosis appear to exist in a wide range of degenerative disease. The free radical theory is tied up in these observations. The situation remains unclear and an area for further work.
Genetic Diseases
Only 13 proteins, all essential for mitochondrial function, 22 transfer RNAs and two ribosomal RNAs are coded by mtDNA which is very compact, rather polymorphic and completely dependent on enzymes coded in the nucleus for DNA replication, repair, transcription and translation.[2] As a large number of the essential proteins in mitochrondria, including these, are part of the normal eukaryote genome, a number of classically inherited mitochrondrial conditions exist (see mitochondrial disorders).
Identical sequences of the millions of mtDNA in an individual is called homoplasty. With many mitochrondrial genetic diseases you will have heteroplasty due to not all mitochondria in the ovum having the same genome or mtDNA having mutated spontaneously in stem cell lines (fair risk given ageing and the metabolic enviroment of a mitochondria). The proportion of heteroplasty may be important in the phenotype. Some familial variants of common neurodegenerative diseases clearly are associated with problems in coding and function of mitochrondrial proteins and the polygenetics of thses diseases themselves seems to suggest mitochrondrial geneome importance potentially.
| Disease | Mutation | Phenotype |
|---|---|---|
| Leber optic atrophy(LHON, Leber's hereditary optic neuropathy) | Eighteen allelic variants. Three mutations at basepairs 11778, 3460, and 14484 in 90% |
|
| Chronic progressive external opthalmoplegia (CPEO) | A spectrum of both direct mitochrondrial genome disease and a number of autosomial dominant and recessive conditions that results in deletions in region of mtDNA between the genes for cytochrome b and cytochrome oxidase subunit II |
|
| *CPEO autosomal dominant 1 | Mutation of nuclear-encoded DNA polymerase-gamma gene (POLG) on chromosome 15q25. | May have cataracts, hearing loss, sensory neuropathy, ataxia, depression, hypogonadism, and parkinsonism |
| *CPEO autosomal dominant 2 | Mutation of adenine nucleotide translocator-1 (ANT-1) gene on chromosome 4q34, | Can have autosomal recessive inheritance which tends to be more severe |
| *CPEO autosomal dominant 3 | Mutation of twinkle gene (C10ORF2) on chromosome 10q24 | Can have autosomal recessive inheritance which tends to be more severe |
| *CPEO autosomal dominant 3 | Mutation of nuclear-encoded DNA polymerase gamma-2 gene (POLG2) on on chromosome 17q. | Autosomal recessive inheritance possible, which tends to be more severe
|
| Kearns-Sayre syndrome (KSS) | Proportion of mutated mtDNA in each KSS patient range from 45 to 75% of total mtDNA. |
|
| Pearson's marrow-pancreas syndrome(Pearson's syndrome) | deletion of nucleotides 9238 to 15575 typically |
|
| MELAS
(Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) | Multiple point mutations possible, in MTTL1, MTTQ, MTTH, MTTK, MTTS1, MTND1, MTND5, and MTND6 genes |
|
| MERRF (Myoclonic epilepsy and ragged-red fibers) | A-to-G mutation at nucleotide 8344 in the gene for transfer RNA for lysine accounts for 80% plus of cases |
|
| NARP(Neuropathy, Ataxia and Retinitis pigmentosa) | Nucleotide 8993 of the MTATP6 gene, resulting in change from highly conserved leucine to arginine in mitochondrial H+-ATPase |
|
| Leigh syndrome (LS) | Caused by a large number of mutations in both nuclear- and mt-DNA genes involved in energy metabolism |
|
| SANDO | Twin mutation in the nuclear-encoded DNA polymerase-gamma gene (POLG) and the C10ORF2 gene |
|
| Alpers syndrome | Mutation of nuclear gene encoding mitochondrial DNA polymerase gamma (POLG) on 15q25 | Usually early onset, but can be early adult life
|
| Cytochrome c oxidase (COX, Complex VI) deficiency | Polygenetic and common. Subunits I, II, and III (MTCO1, MTCO2, MTCO3) are encoded by mtDNA while subunits IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, VIIc, and VIII are nuclear encoded. |
|
| GRACILE | Mutation in the BCS1L gene on 2q33 |
|
| PARK6 | Mutations in the PINK1 gene which codes for a mitochrondrial protein |
|
| Parkinson's disease | Polygenetic but none consistent and may be acquired | Parkinsonism |
| Alzheimer's disease | Polygenetic but none consistent except interaction Amyloid β with Aβ-binding alcohol dehydronase (ABAD). May be acquired | Dementia, apoptosis |
| Motor neurone disease | Polygenetic and may be acquired. Import of Superoxide dysmutase-1 (SOD-1) into mitochondria impaired in familial MND | |
| Friedreich's ataxia | GAA repeats of gene encoding for Frataxin, protein involved in mitochondrial haem and iron-sulphur protin synthesis | |
| Ageing | Polygenetic, early senescene with some deficient POLG genotypes | |
| Malignancy -colon, prostate | Polygenetic including MTCOX1 | |
| Diabetes mellitus | Associations with decreased mitochrondrial function not yet characterised well. |
Treatment implications
- High dose coenzyme Q10 has been tried in a number of these conditions with mild to moderate preliminary success
- Potential for N-acetylcysteine from animal models in NARP or LS
- Manipulation of mtDNA
- Cytoplasmic transfer into oocyte- failing to live up to promise due to chromosome mutation
- Pronuclear transfer between single-cell embryos
