Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

Abstract

Mitochondrial DNA (mtDNA) deletions are a common cause of human mitochondrial diseases. Mutations in the genes encoding components of the mitochondrial replisome, such as DNA polymerase gamma (Pol g) and the mtDNA helicase Twinkle, have been associated with the accumulation of such deletions and the development of pathological conditions in humans. Recently, we demonstrated that changes in the level of wild-type Twinkle promote mtDNA deletions, which implies that not only mutations in, but also dysregulation of the stoichiometry between the replisome components is potentially pathogenic. The mechanism(s) by which alterations to the replisome function generate mtDNA deletions is(are) currently under debate. It is commonly accepted that stalling of the replication fork at sites likely to form secondary structures precedes the deletion formation. The secondary structural elements can be bypassed by the replication-slippage mechanism. Otherwise, stalling of the replication fork can generate single-and double-strand breaks, which can be repaired through recombination leading to the elimination of segments between the recombination sites. Here, we discuss aberrances of the replisome in the context of the two debated outcomes, and suggest new mechanistic explanations based on replication restart and template switching that could account for all the deletion types reported for patients.

Therapy Prospects for Mitochondrial DNA Maintenance Disorders

“…mtDNA replication is entirely dependent on nuclear encoded proteins that are synthesized in the cytosol and imported into mitochondria. Interestingly, mutations in genes encoding most of the factors constituting the mtDNA replisome [ 48 , 49 ] have been associated with MDDS ( Table 1 ). Since the first identification of mutations in POLG [ 16 ] and TWNK [ 18 ] as causative of MDDS in 2001, a total of 10 genes encoding proteins directly involved in mtDNA replication and repair machinery have been incorporated in this list to date, including the recent identification of mutations in LIG3 causing a mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) like phenotype [ 25 ].…”

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

“…The maintenance of mtDNA requires a variety of nDNA-encoded gene products. The proteins involved in mtDNA replication have been termed replisome [50]. The mtDNA replisome consists of the mtDNA polymerase γ (a complex of POLG and POLG2 gene products), the mitochondrial transcription factor (TFAM), the DNA helicase twinkle (TWNK), and the mitochondrial single-stranded binding protein (mtSSB) [50].…”

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

“…The maintenance of mtDNA requires a variety of nDNA-encoded gene products. The proteins involved in mtDNA replication have been termed replisome [50]. The mtDNA replisome consists of the mtDNA polymerase gamma (a complex of POLG and POLG2 gene products), the mitochondrial transcription factor (TFAM), the DNA helicase twinkle (TWNK), and the mitochondrial single-stranded binding protein (mtSSB) [50].…”

“…The proteins involved in mtDNA replication have been termed replisome [50]. The mtDNA replisome consists of the mtDNA polymerase gamma (a complex of POLG and POLG2 gene products), the mitochondrial transcription factor (TFAM), the DNA helicase twinkle (TWNK), and the mitochondrial single-stranded binding protein (mtSSB) [50]. Remarkably, variants in POLG, TWNK, and TFAM are not only known as a monogenic cause of primary mitochondrial disorders (occasionally presenting with parkinsonism) but can also increase the risk for PD [51].…”