Defects of Mitochondrial DNA Replication

Abstract

Mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. 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, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mtDNA and mitochondrial disease.

Maintenance and Expression of Mammalian Mitochondrial DNA

“…A large number of pathogenic mutations have been reported in the genes encoding POLγA and TWINKLE, and some mutations have also been found in the gene encoding POLγB (109). Affected patients display deletions or depletion of mtDNA that lead to respiratory-chain deficiency and neuromuscular symptoms: Progressive external ophthalmoplegia, exercise intolerance, and muscle weakness are common symptoms (109).…”

Mitochondrial Single-stranded DNA-binding Proteins Stimulate the Activity of DNA Polymerase γ by Organization of the Template DNA

“…Pol ␥ dysfunction is the major cause of human mitochondrial diseases, for which there is no direct treatment currently available (16). Understanding how mtSSB stimulates Pol ␥ may contribute to developing treatment strategies based on enhancing Pol ␥ activity.…”

Inherited mitochondrial genomic instability and chemical exposures

“…Most mtDNA diseases predominantly affect the nervous system, which in large part is due to the high energy requirements of neurons, and the polar shape of neurons requiring mitochondria to travel larger distances than many other cell types (Chen and Chan 2009; Lax et al 2017; Schwarz 2013). MtDNA diseases include childhood-onset Leigh syndrome and Alpers syndrome, as well as later onset ataxia-neuropathy spectrum disorders, and progressive external ophthalmoplegia (Copeland 2014; Naviaux 2004; Stewart and Chinnery 2015; Wallace 1999). In addition to these rarer disorders, mtDNA instability has also been associated with Parkinson’s Disease, cancer and ageing (Zapico and Ubelaker 2013).…”

“…Furthermore, mtDNA instability can be exacerbated by faulty mtDNA replication-associated proteins. In fact, several mitochondrial disease loci encode proteins that are directly and indirectly required for mtDNA replication (Copeland 2014). The three main proteins most directly involved in mtDNA replication with associated human disease mutations are POLG (the catalytic subunit of the mtDNA polymerase, DNA polymerase gamma), POLG2 (the accessory subunit of DNA polymerase gamma), and TWNK (alternatively known as PEO1, the mtDNA helicase).…”