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

Defects in mitochondrial DNA replication and human disease.

Author information

1
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, North Carolina 27709, USA. copelan1@niehs.nih.gov

Abstract

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.

PMID:
22176657
PMCID:
PMC3244805
DOI:
10.3109/10409238.2011.632763
[Indexed for MEDLINE]
Free PMC Article

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