Mitochondrial Mutations

 

 

Introduction

 

Mitochondria are double membrane bound intracellular organelles responsible for various mechanisms of cellular organisms including supporting aerobic respiration and providing metabolic pathways with energy [SALVATORE & SCHON, 2003]. Mitochondria produces energy in the form of adenosine triphosphate (ATP) to fuel cellular mechanisms required for cell survival.

ATP is the main product of the respiratory chain-oxidative phosphorylation system (OXPHOS) [SCHON, 2000] which involves an electron transport chain (ETC). The ETC occurs on the inner mitochondrial membrane which contains five multimeric protein complexes also known as the respiratory complexes [SALVATORE & SCHON, 2003].

Figure 1 illustrates the components of the respiratory chain [SCHAPIRA, 2006].

 

Mitochondrial Inheritance

 

Mitochondria are almost exclusively maternally inherited in mammals [BLANC et al, 1980]. That means they do not follow the normal Mendelian patterns of inheritance where a paternal genetic component will have an equal influence as the maternal genetic component over the heteroplasmic phenotype produced. Instead, the inheritance pattern is complex.

Generally, the mitochondrial genome is homoplasmic due to its maternally inherited nature but may become heteroplasmic as mutations arise. A study done on 9 generations of mice was undertaken by Gyllensten et al (1985). It proved the inheritance pattern of mitochondria creates a lack of genetic variability. This causes heteroplasmic mitochondria to be reverted back to homoplasmic after several generations.

A study was undertaken by Dominko et al (2000) to investigate the reason as to why mitochondria are 99.9% maternally inherited. The study proved paternal mitochondria were destroyed shortly after fertilisation through a process called ubiquination. Paternal mitochondria obtain the proteolytic marker ubiquitin during spermatogenesis which enables for their destruction once they’re inside the oocyte cytoplasm [DOMINKO et al, 2000].

Exclusively maternally inherited mitochondria suggest mitochondrial mutations are also maternally inherited.

 

The cause of mitochondrial mutations

 

Like all cellular components, mitochondria rely on its cellular environment in order to function the way it is supposed to. Deficiencies, hyper activity or mutant cellular components have the ability to produce a mitochondrial phenotype different to its wild-type. An abnormal phenotype could effectively cause defective protein assembly or stability [SCHAPIRA, 2006] which consequently leads to respiratory chain-linked disorders.

The most common cause of mitochondrial mutations is associated with the deficiency of cytochrome oxidase (COX) [WALLACE, 1999]. The nuclear genes SCO2, SURF1, COX10, COX15 and LRPPRC responsible for the production of mitochondrial proteins involved with the assembly and maintenance of COX have been identified as the source of mutation causing COX deficiency. COX deficiency results in pathogenic phenotypes related to mitochondria such as myopathy, encephalopathy, lactic acidosis, motor neurodegenerative diseases and anaemia [SCHAPIRA, 2006]. These phenotypes are the result of a defective OXPHOS.

Another cause of defective OXPHOS is the deficiency of Coenzyme Q₁₀.  Coenzyme Q₁₀ is a component of the respiratory chain which transfers electrons between complexes I and II as well as between fatty acids and unbranched amino acid chain to complex III via flavin-linked dehydrogenases [SCHAPIRA, 2006]. The effect of Coenzyme Q₁₀ deficiency could result in cerebellar atrophy and potentially encephalomyopathy, seizures, weakness, myopathy and ataxia [SCHAPIRA, 2006].

Less commonly identified causes of defective respiratory chain components include mutations in the BSC1L and ATP12 genes. BSC1L causes complex III to assemble incorrectly which has been known to potentially result in Leigh’s syndrome, growth retardation, lactic acidosis and early death. ATP12 mutants on the other hand can cause a deficiency of complex V [SCHAPIRA, 2006].

Mitochondrial disorders arise from missence mutations obtained by mitochondrial DNA (mtDNA) and mitochondrial protein encoding nucleic DNA (nDNA) [YAFFE, 1999] during oogenesis.

 

Mitochondrial DNA (mtDNA)

 

Mammalian mtDNA is a 16.6 kb double stranded circular DNA genome which encodes for 22 tRNA genes for the synthesis of mitochondrial protein, the 12S and 16S rRNA genes for mitochondrial ribosomes and 13 subunits of the respiratory chain [WALLACE, 1999]. Of the respiratory complexes, it encodes for:

·         - Seven subunits of complex I

·         - Three subunits of complex IV

·         - Two subunits of complex V

·         - Cytochrome b (a subunit of complex III)

Mutations affecting respiratory complexes ultimately results in a defective OXPHOS or the build up of toxic reactive oxygen species (ROS) which in turn lead to a variety of mitochondrial disorders and premature cell death (apoptosis) [WALLACE, 1999].

Disorders caused by mutational mtDNA tend to either be sporadic large scale rearrangements or point mutations [SPINAZZOLA & ZEVIANI, 2003].

 

mtDNA multiple gene deletions

 

Disorders associated with large scale deletions of the mitochondrial genome are sporadic because the same mutations may not exist in the mother or siblings. Typically, the affected region is between the genes encoding for cytochrome b through to COI. Clinical disorders associated with these large scale deletions may exhibit all or only some of the gene deletions [SCHON, 2000]. The deletions range from 2 to 10 kb [SALVATORE & SCHON, 2003].This means that all the complexes of the respiratory chain could be potentially affected by mutational mtDNA (with the exception of complex II) as well as the synthesis of some mitochondrial proteins. Disorders caused by large scale deletions are neurological and include:

 

Chronic progressive external opthalmoplegia (CPEO)

CPEO is a neurological disease which affects skeletal muscles [SCHON, 2003]. It is clinically characterised by mitochondrial myopathy including opthalmoplegia and ptosis [WALLACE, 2000]. Patients characteristically possess droopy eyes due to the paralysis of ocular muscles. On a molecular level, the muscle fibres affected by CPEO generally have a deficiency in cytochrome oxidase (COX) as well as hyper activity of succinate dehydrogenase (SDH) [WALLACE, 1999]resulting in proliferating muscles containing defective mitochondria also known as  red ragged fibres (RRF’s) [SUDBERY, 2002].

 

Kearns Sayre Syndrome (KSS)

KSS is a severe multisystemic disorder [SCHON, 2000] which is caused by neuromuscular dysfunction [The Nation institute of Neurological disorders and Stroke, 2007].  KSS exhibits the same clinical symptoms as CPEO as well as ataxia, retinal deterioration, cardiac defects, deafness, renal problems and diabetes mellitus [WALLACE, 1999]. The molecular basis of KSS is the same as that of CPEO. Patients with KSS normally develop the progressively slow neuromuscular disease before the age of 20 [The Nation institute of Neurological disorders and Stroke, 2007].

Pearson’s Syndrome (PS)

 

PS is a fatal neurological disorder which could also be classified as a hematopoeitic disease [SCHON, 2003]. Patients with PS are distinctively unable to produce blood cells due to marrow dysfunction. PS ultimately leads to pancytopenia (complete loss of blood cells) which accounts for the low prognosis of only a few years.  PS only affects children and unlike CPEO and KSS, it progresses rapidly. PS could result in severe anaemia and other blood disorders as well as pancreatic failure [SUDBERY, 2002].

The molecular basis of CPEO, KSS and PS are virtually the same. That is, they occur as a result of multiple mtDNA gene deletions during oogenesis. The differing symptoms between the three diseases are a result of the segregation of the mutational mtDNA across germ layers. Uniform segregation into all germ layers would result in KSS, non uniform segregation would result in PS and finally, CPEO is the result of segregation only into muscle cells [SCHON, 2000].

 

mtDNA point mutations

 

Disorders caused by mtDNA point mutations typically involve a base pair substitution [WALLACE, 2000]. Mitochondria are considered are considered to be genotypically heteroplasmic when mtDNA mutations occur.  Disorders resulting from mtDNA point mutations include:

 

 

Leber’s hereditary optic neuropathy (LHON) 

LHON is the most common disorder resulting from mtDNA mutations [SCHAPIRA, 2006]. It is an OXPHOS disease which affects the ND4 and ND6 genes which encodes for the production of complex I (NADH dehydrogenase) subunits. LHON is clinically characterised by the degeneration of retinal ganglion cells and their axons which cause blindness [SCHAPIRA, 2006].

 

Leigh’s Syndrome 

Leigh’s syndrome is a more serious neurodegenerative disorder associated with the loss of motor and verbal skills [SUDBERY, 2002]. It is caused by mutations of the ATPase6 gene which encode for complex V (ATP synthase) [SCHAPIRA, 2006]. Patients with LHON possess a mental retardation caused by degeneration of the basal ganglia. 

 

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) 

MELAS typically affects the tissues of the CNS and causes brain dysfunction. It is clinically characterised by epilepsy and seizures, cardiomyopathy, mitochondrial encephalomyopathy, lactic acidosis and deafness [SCHON, 2000]. It is commonly caused by the MTTL1*MELAS3243G mutation at the tRNA Leucine encoding gene [WALLACE, 2000].

  

Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) 

NARP is a disorder caused by an ATPase6 mutation which results in muscle weakness as well as blindness [SUDBERY, 2002].

 

 

Figure 2.a Outlines the common mitochondrial mutations associated with mtDNA and nDNA mutations affecting the OXPHOS respiratory chain complexes [SCHON, 2000].

Figure 2.b The sites of genomic mtDNA mutations prone to producing certain mitochondrial diseases [WALLACE, 1999].

 

 

Genotype-Phenotype of Mitochondrial diseases 

 

The relationship between the genotype and phenotype of mitochondrial diseases is complex considering different mutations may cause the same phenotype and single mutations could cause similar phenotypes e.g. LHON and dystonia phenotypes can be caused by the same MTND6*LDYT14459A mutation involving the substitution of the G base to A in the mitochondrial ND6 gene [SPINAZZOLA & ZEVIANI, 2003]. Phenotypes not only depend on genotypic mutations but also the nuclear background, tissue distribution, levels of heteroplasmy and OXPHOS requirements. 

 

 

Figure 3. Common mutations associated with different mitochondrial disease phenotypes [SPINAZZOLA & ZEVIANI, 2003]

 

Prevalance and Prognosis

 

Mitochondria have a long evolutionary history and it has been theorised that mitochondria had once existed extracellularly, accountiong for its double membrane-bound characteristic. The phenotypes of mutations are overall quite different but similarities could be seen between mitochondria of people with similar genetic history (i.e. of the same race). The prevalance and prognosis of mitochondrial diseases also vary.

Adults above the age of 40 have a higher prevalance in obtaining mitochondrial mutations. Certain mitochondrial diseases also have a higher prevalance than others. LHON has a prevalance of 11.82 per a population of 100 000 whereas single deletions have a prevalance of 1.2 per 100 000 [SCHAPIRA, 2006]. A higher prevalance in single point mitochondrial mutations is due to easier base substitutions rather than large genomic deletions. The higher prevalance in adults could be due to a relationship between the symptoms of old age and mitochondrial diseases.

Prognosis of the many types of mitochondrial diseases also vary. It varies between the age of onset as well as the type of mutations obtained. The severity of mitochondrial diseases in certain areas of the body directy correlate to the OXPHOS requirements of specific organs and tissues. The more a tissue depends on OXPHOS for energy, the higher the concentration of defective mitochondria and thus more severe clinical symptoms [SCHAPIRA, 2006].

Children have a lower prognosis to mitochondrial mutations. It can be reasoned that the difference in tissue distribution accounts for this.

 

The relationship between mitochondrial mutations and ageing

 

Mitochondrial diseases have been known to exhibit the same clinical symptoms with that associate with ageing. Such symptoms include deteriorating vision, muscle weakness and deafness [KOEHLER et al, 1999]. Neurodegenerative diseases such as Alzheimers and Parkinson's disease are also diseases which have been associated with both old age and mitochondrial mutations.

 

Treatment

 

No effective treatment exists for management of mitochondrial mutations. There have been studies which aim at finding substitutions and supplements for defective respiratory complexes in order to promote a healthy OXPHOS e.g. riboflavin is used as a precursor for complexes I and II [MAHONEY et al, 2002].

In prevention, Coenzyme Q₁₀ is effectively administered to patients with mitochondrial mutations which are caused by a deficiency in coenzyme Q_10.

 

References

 

- Koehler, C.M., Leuenberger, D., Merchant, S., Renold, A., Junne, T. & Schattz, G. 'Human Deafness Dystonia Syndrome Is a Mitochondrial Disease' (1999) Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 5 pp. 2141-2146

- Schapira, A.H.V. 'Mitochondrial Disease'  (2006) The Lancet Vol. 386

- Wallace, D.C. 'Mitochondrial defects in cardiomyopathy and neuromuscular disease' (2000) American Heart Journal, Vol 139, No 2 [3]

- Yaffe, M.P 'The Machinery of Mitochondrial Inheritance and Behavior' (1999) Science Vol 283

- Spinazzola, A. & Zeviani, M. 'Mitochondrial disorders' (2003) Current Neurology and Neuroscience Reports Vol 3 pp 423–432

- Wallace, D.C. 'Mitochondrial Diseases in Man and Mouse' (1999) Science Vol. 283; 1482

- Schon, E.A. 'Mitochondrial genetics and disease' (2000) TIBS Vol. 25

- Dominko, T., Moreno, R.D, Santos, J.R, Schatten, G., Simerly, C. & Sutovsky, P. 'Ubiquitinated Sperm Mitochondria, Selective Proteolysis, and the Regulation of Mitochondrial Inheritance in Mammalian Embryos' (2000) Biology of reproduction Vol. 63, pp 582–590

- Blanc, H. Cann, H.M., Giles, R.E. & Wallace, D.C. 'Maternal Inheritance of Human Mitochondrial DNA' (1980) Proceedings of the National Academy of Sciences of the United States of America,Vol. 77, No. 11, [2] pp. 6715-6719

- Gyllensten, U., Wharton D. & Wilson, A.D. 'Maternal inheritance of mitochondrial DNA during backcrossing of two species of mice' (1985) The Journal of Heredity Vol 76 pp 321-324

- Schon, E.A & DeMauro, S. ' Mitochondrial respiratory-chain disorders' (2003) The New England Journal of Medicine Vol 348

- Mahoney, D.J., Parise, G. & Tarnopolsky, M.A. 'Nutritional and exercise-based therapies in the treatment of mitochondrial diseases' (2002) The current opinion in clinical nutrition and metabolic care Vol. 5

- The National Institute of Neurological disorders and Stroke' http://www.ninds.nih.gov/disorders/kearns_sayre/kearns_sayre.htm Last updated: 13/02/2007. Date accessed: 27/09/09