- Mitochondrial DNA (mtDNA) replication occurs independently from nuclear DNA replication and can take place even in non-dividing cells. The process begins at a specific region called the D-loop, which contains the origin of heavy strand replication (OH).
- The initial step involves the mitochondrial RNA polymerase creating an RNA primer at the OH site. This primer allows DNA polymerase gamma (pol γ), the main mitochondrial DNA polymerase, to begin synthesizing the new heavy strand. As replication proceeds, the parental DNA strands separate, and the replication machinery moves along the template.
- When the replication fork reaches about two-thirds of the way around the circular mtDNA molecule, it exposes the origin of light strand replication (OL). This triggers the synthesis of the complementary light strand, but in the opposite direction. This creates an unusual asymmetric replication model where heavy and light strand synthesis occur at different times and rates.
- DNA polymerase gamma works in conjunction with several other proteins, including the mitochondrial single-stranded DNA-binding protein (mtSSB), which stabilizes single-stranded regions, and the mitochondrial helicase Twinkle, which unwinds the double-stranded DNA ahead of the replication fork.
- The entire process ends when both strands are completely replicated, resulting in two identical copies of the circular mtDNA molecule. This replication system is notably different from nuclear DNA replication and is more prone to mutations, which can lead to various mitochondrial diseases.
