Defects in mitochondrial DNA replication and human disease

Crit Rev Biochem Mol Biol. 2012 Jan-Feb;47(1):64-74. doi: 10.3109/10409238.2011.632763.


Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • DNA Helicases / genetics
  • DNA Polymerase gamma
  • DNA Replication / genetics*
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Diffuse Cerebral Sclerosis of Schilder / genetics
  • Humans
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Proteins
  • Mutation / genetics*
  • Neurodegenerative Diseases / genetics*
  • Nucleotides / metabolism
  • Ophthalmoplegia, Chronic Progressive External / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Ribonucleotide Reductases / metabolism
  • Thymidine Kinase / metabolism
  • Thymidine Phosphorylase / metabolism


  • Cell Cycle Proteins
  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Nucleotides
  • RRM2B protein, human
  • Ribonucleotide Reductases
  • TYMP protein, human
  • Thymidine Phosphorylase
  • Phosphotransferases (Alcohol Group Acceptor)
  • thymidine kinase 2
  • deoxyguanosine kinase
  • Thymidine Kinase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human
  • POLG2 protein, human
  • DNA Helicases
  • TWNK protein, human