Defects in mitochondrial DNA replication and human disease

Abstract

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA 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 (MDS) 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.

DNA Sequences Proximal to Human Mitochondrial DNA Deletion Breakpoints Prevalent in Human Disease Form G-quadruplexes, a Class of DNA Structures Inefficiently Unwound by the Mitochondrial Replicative Twinkle Helicase

“…Mitochondrial G4 DNA and Genetic Disease-Mutations in several nuclear genes are associated with the mitochondrial DNA instability of PEO patients, including genes encoding the mitochondrial DNA polymerase ␥ and its accessory subunit, Twinkle/C10orf2 mitochondrial helicase, the RRM2B ribonucleotide reductase subunit, and the adenine nucleotide translocator (48). Interestingly, a recent study by Roos et al (49) described a sibling pair with compound heterozygous POLG1 mutations that displayed PEO, cognitive impairment, and mitochondrial myopathy, characterized by multiple mitochondrial deletions.…”

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

“…Genes associated with MDS encode proteins involved in maintenance of the mitochondrial nucleotide pool or in mtDNA replication (Copeland 2012;El-Hattab and Scaglia 2013), as observed for chromosome 10 open reading frame 2 (C10Orf2), also called Twinkle.…”

Mouse models of DNA polymerases

“…Lewis et al developed a mouse in which the Y955C variant of Pol g [Lewis et al, 2007]. In humans, Y955C Pol g is the most common and severe autosomal dominant mutation in POLG that is also associated with the mitochondrial diseases of chronic progressive external opthalmoplegia (CPEO), Parkinsonism, and premature ovarian failure [Copeland, 2012]. Biochemically, the Y955 residue interacts with the incoming dNTP and the Y955C mutation results in decreased fidelity thereby rendering Y955C Pol g a mutator polymerase.…”