Editing Mitochondrial DNA (section)

== Replication ==
The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand.<ref name=":0">{{Cite journal |last1=Berk |first1=Arnold J. |last2=Clayton |first2=David A. |date=1974-07-15 |title=Mechanism of mitochondrial DNA replication in mouse L-cells: Asynchronous replication of strands, segregation of circular daughter molecules, aspects of topology and turnover of an initiation sequence |url=https://linkinghub.elsevier.com/retrieve/pii/0022283674903556 |journal=Journal of Molecular Biology |volume=86 |issue=4 |pages=801–824 |doi=10.1016/0022-2836(74)90355-6 |pmid=4473554 |issn=0022-2836}}</ref> The regulation of mitochondrial DNA replication and transcription initiation is located in a single intergenic noncoding region (NCR).<ref name=":0" /> In human, the 1,100 base pairs NCR region contains three promoters of two L-strand promoters (LSP and LSP2) and one H-strand promoter (HSP).<ref>{{Cite journal |last1=Tan |first1=Benedict G. |last2=Mutti |first2=Christian D. |last3=Shi |first3=Yonghong |last4=Xie |first4=Xie |last5=Zhu |first5=Xuefeng |last6=Silva-Pinheiro |first6=Pedro |last7=Menger |first7=Katja E. |last8=Díaz-Maldonado |first8=Héctor |last9=Wei |first9=Wei |last10=Nicholls |first10=Thomas J. |last11=Chinnery |first11=Patrick F. |last12=Minczuk |first12=Michal |last13=Falkenberg |first13=Maria |last14=Gustafsson |first14=Claes M. |date=2022-10-06 |title=The human mitochondrial genome contains a second light strand promoter |url=https://linkinghub.elsevier.com/retrieve/pii/S109727652200764X |journal=Molecular Cell |language=English |volume=82 |issue=19 |pages=3646–3660.e9 |doi=10.1016/j.molcel.2022.08.011 |issn=1097-2765 |pmid=36044900}}</ref> Unlike bidirectional and specific origin initiation of nuclear DNA replication, mitochondrial DNA has two strand-specific, unidirectional origins of replication of the leading H strand (O<sub>H</sub>) which located in NCR and the lagging L strand (O<sub>L</sub>) which located in the tRNA gene cluster.<ref>{{Cite journal |last1=Robberson |first1=Donald L. |last2=Kasamatsu |first2=Harumi |last3=Vinograd |first3=Jerome |date=March 1972 |title=Replication of Mitochondrial DNA. Circular Replicative Intermediates in Mouse L Cells |journal=Proceedings of the National Academy of Sciences |volume=69 |issue=3 |pages=737–741 |doi=10.1073/pnas.69.3.737 |doi-access=free |pmc=426547 |pmid=4501588|bibcode=1972PNAS...69..737R }}</ref>

Mitochondrial DNA is replicated by the [[DNA polymerase]] gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the ''[[POLG]]'' gene and two 55 kDa accessory subunits encoded by the ''[[POLG2]]'' gene.<ref>{{Cite journal |vauthors=Yakubovskaya E, Chen Z, Carrodeguas JA, Kisker C, Bogenhagen DF |date=January 2006 |title=Functional human mitochondrial DNA polymerase gamma forms a heterotrimer |journal=The Journal of Biological Chemistry |volume=281 |issue=1 |pages=374–382 |doi=10.1074/jbc.M509730200 |pmid=16263719 |doi-access=free}}</ref> The [[replisome]] machinery is formed by DNA polymerase, [[PEO1|TWINKLE]] and mitochondrial [[SSB protein]]s. TWINKLE is a [[helicase]], which unwinds short stretches of dsDNA in the 5' to 3' direction.<ref name="Jemt2011">{{Cite journal |author-link6=Maria Falkenberg |vauthors=Jemt E, Farge G, Bäckström S, Holmlund T, Gustafsson CM, Falkenberg M |date=November 2011 |title=The mitochondrial DNA helicase TWINKLE can assemble on a closed circular template and support initiation of DNA synthesis |journal=Nucleic Acids Research |volume=39 |issue=21 |pages=9238–9249 |doi=10.1093/nar/gkr653 |pmc=3241658 |pmid=21840902}}</ref> All these polypeptides are encoded in the nuclear genome.{{cn|date=November 2024}}

During [[embryogenesis]], replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo.<ref name="John2010" /> The resulting reduction in per-cell copy number of mtDNA plays a role in the mitochondrial bottleneck, exploiting [[cellular noise|cell-to-cell variability]] to ameliorate the inheritance of damaging mutations.<ref name="pmid26035426" /> According to Justin St. John and colleagues, "At the [[blastocyst]] stage, the onset of mtDNA replication is specific to the cells of the [[trophectoderm]].<ref name="John2010" /> In contrast, the cells of the [[inner cell mass]] restrict mtDNA replication until they receive the [[Cell signaling|signals]] to [[Cellular differentiation|differentiate]] to specific cell types."<ref name="John2010">{{Cite journal |vauthors=St John JC, Facucho-Oliveira J, Jiang Y, Kelly R, Salah R |year=2010 |title=Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells |journal=Human Reproduction Update |volume=16 |issue=5 |pages=488–509 |doi=10.1093/humupd/dmq002 |pmid=20231166 |doi-access=free}}</ref>