Mitochondrial diseases

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Mitochondrial genome.

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 [1]). There are many other mitochondrial disorders considered in detail elsewhere. For example some forms of genetic Parkinsons disease.


Toxin Induced Diseases

  • Mitochondrial Complex I
    • MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Designer drug Parkinsonism)
    • Anonnacin. rotenone and tetrahydroisoquinolines
    • Deficiency induced in Parkin postive familiar Parkinsons
  • Mitochondrial Complex IV (13 polypeptides)-Four redox centres, 2 heme centres (a and a3) and 2 copper centres (CuA and CuB)

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

Most genetic conditions are transmitted in the nuclear DNA.Such conditions can be inherited in an autosomal or X-linked manner.

mtDNA diseases

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.[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). 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.

Commoner Mitochondrial genetic diseases due to defects in mitochondrial genome
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%
  • Mid-life acute or subacute central vision loss (central scotoma progressing to blindness
  • The 14484 mutation has a good visual prognosis
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
  • Progressive external ophthalmoplegia
  • Myopathy
  • Multiple other phenotypes as is whole group of diseases of heterogenous cause
*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
  • Male subfertility
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
  • Refractory sideroblastic anaemia
  • Vacuolization of marrow precursors
  • Exocrine pancreatic dysfunction
  • Can progress/evolve to KSS

(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
  • Sensory ataxic neuropathy,
  • Dysarthria
  • Ophthalmoparesis
Alpers syndrome Mutation of nuclear gene encoding mitochondrial DNA polymerase gamma (POLG) on 15q25 Usually early onset, but can be early adult life
  • Psychomotor retardation
  • Intractable epilepsy
  • Liver failure due to micronodular cirrhosis
  • Cortical blindness
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.
  • Variants are associated with normal (wild) range of human exercise capacity
  • Association with late onset Alzheimer's disease
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.

Treatment implications

  • 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
    • As of 2015 the technology is unpredictable and offers only temporary response[3]
  • 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[4], 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


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