Human Mitochondrial DNA

BY: Ezhuthachan Mithu Mohanan (MIWM043)

DNA within mitochondria was first detected in 1963. Human mitochondria represent the mammalian mtDNA. Human mtDNA is 16,569 bp, double stranded and circular. It codes for 13 polypeptides, belonging to OXPHOS family. mtDNA also codes for 22 tRNA,2 rRNA. It also has control noncoding regions. Various nuclear coded factors also known as precursor polypeptides are essential for the expression and maintenance of mtDNA. It was Sanger who found that circular mtDNA in vertebrates, has both Light Strand and Heavy strand. There are many differences considering nuclear DNA and mitochondrial DNA, which are as follows 

Present in mitochondria Present in nucleous
One cell contains 0.25% mtDNAOne cell has 99.75% n DNA
Mutation rate of mtDNA is 20 times faster than nDNASlow mutation rate 
circular Linear
1000’s of mtDNA copies/ cell2 Copies / cell
Maternally inherited Biparental inheritance
Replication repair mechanism is absent Replication repair mechanism is present
Reference sequence by Anderson  and Colleagues in 1981Reference sequence in Human Genome Project in 2001
Size of genome is 16,569 bp Size of genome is 3.2 billion base pair

The genetic code of nuclear DNA differ from mtDNA as such ‘TGA’ codes for tryptophan in vertebrate mitochondria, while it is a stop codon for nuclear DNA. ‘ATA’ codes for Isoleucine in cytosol, while it codes for methionine in mitochondria.

Mitochondrial Inheritance: 

With most of the evidence provided, mostly there is maternal inheritance of mitochondria. Due to nucleotide imbalance and reduction in fidelity of polymerase γ, it causes higher mutation rate. This can be used as approach for human identity test, studying evolutionary and migration pattern.

mtDNA replication:  

Factors for mtDNA  replication: 

DNA Polymerase γ is the polymerase enzyme, it is a heterotrimer with one catalytic subunit ( POLγA). POLγA has 3’-5’ exonuclease activity for proofreading. TWINKLE is DNA Helicase which unwinds double stranded DNA. mtSSB is binds with single stranded DNA to protect from nucleases. Vinograd and coworkers proposed the strand displacement theory, which emphasize continuous DNA synthesis on H and O strand. The replication initiation begins from OH Strand, which proceeds unidirectional. During OL replication stem loop structure is formed which block mtSSB from binding, initiating primer synthesis. Thus the two strand synthesis occur in a continuous manner , until two complete double stranded DNA is formed.A triple-stranded displacement loop structure also known as D Loop is formed, When 7S DNA remains bound to parental L strand, while parental H-Strand is displaced.  The role of mtDNA D loop is not completely understood. 

Mitochondrial Diseases:

A dysfunction in mitochondria leads to mitochondrial disorder. Heteroplasmy  is condition due to presence of mutant mitochondrial DNA .  Various Mitochondrial disorders are as follows:

  1. Mitochondrial Myopathy:  Presence of ragged red muscle fibres is due to accumulation glycogen and neutral lipids which leads to decreased reactivity of cytochrome c oxidase
  2. Leber’s hereditary optic neuropathy : This is maternally inherited, which causes degeneration of retinal ganglion cells
  3. Leigh syndrome: It is a neurometabolic disorder affecting CNS( central nervous system)
  4. Myoneurogenic gastrointestinal encephalopathy : Autosomal recessive disorder. It is due to mutation of TYMP gene
  5. Mitochondrial DNA depletion syndrome: It is also known as Aplers disease. This is caused my mutation inTK2 gene.

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