The characteristics of mitochondria with their key contributions to oxidative phosphorylation and cell apoptosis ensure a number of diseases due to toxins involve the mitochondria. 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 ). There are many other mitochondrial disorders considered in detail elsewhere. For example some forms of genetic Parkinsons disease.
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)
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.
Most genetic conditions are transmitted in the nuclear DNA.Such conditions can be inherited in an autosomal or X-linked manner.
Only 13 proteins, all essential for mitochondrial function, 22 transfer RNAs and two ribosomal RNAs are coded by the 37 genes in mtDNA which is very compact, rather polymorphic and completely dependent on enzymes coded in the nucleus for DNA replication, repair, transcription and translation. 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). These conditions are inherited maternally.
Identical sequences of the millions of mtDNA in an individual is called homoplasty. With many mitochondrial 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 mitochondrial proteins and the polygenetics of thses diseases themselves seems to suggest mitochrondrial geneome importance potentially.
|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 mitochondrial 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||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 mitochondrial 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 mitochondrial function not yet characterised well.|
- High dose coenzyme Q10 and its analogues such as idebenone 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
- Gene transfer by viral vectors
- Mitochondrial replacement techniques (MRTs)
- Cytoplasmic transfer into oocyte- failing to live up to promise due to chromosome mutation
- Maternal spindle transfer - Pre-fertilisation nuclear material transfer into donor oocyte (which thus provides almost all the mitochondria)
- Pronuclear transfer between single-cell embryos (post fertilisation)
As some of these MRTs appear to work in animal models (indeed promoting oocyte viability potentially, they may well be tried soon in man. Such preliminary studies are likely ethically to be restricted to males initially to minimise chance any unexpected (epi-) genetic issues being transmitted to offspring
- ↑ DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003 Jun 26;348(26):2656-68. Review.
- ↑ Chen XJ, Butow RA. The organization and inheritance of the mitochondrial genome. Nat Rev Genet. 2005 Nov;6(11):815-25. Review.
- ↑ Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR. Long-Term Effect of Gene Therapy on Leber's Congenital Amaurosis. The New England journal of medicine. 2015 May 14; 372(20):1887-1897.(Link to article – subscription may be required.)
- ↑ Cagnone GL, Tsai TS, Makanji Y, Matthews P, Gould J, Bonkowski MS, Elgass KD, Wong AS, Wu LE, McKenzie M, Sinclair DA, John JC. Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency. Scientific reports. 2016; 6:23229.(Epub) (Link to article – subscription may be required.)