Mitochondrial DNA synthesis pathway (mtDNA synthesis pathway)

The mitochondrial DNA (mtDNA) synthesis pathway is the essential biological process responsible for replicating and maintaining the small, circular genome located within mitochondria (Gaspari et al., 2020, Nature Reviews Molecular Cell Biology). This pathway is primarily driven by the mitochondrial DNA polymerase gamma (POLG), the only DNA polymerase found in human mitochondria, along with the Twinkle helicase (TWNK) and mitochondrial single-stranded DNA-binding protein (mtSSB) (Young, 2017, Cold Spring Harbor Perspectives in Biology). While critical for cellular energy production via oxidative phosphorylation, this pathway is a significant site of drug-induced toxicity, particularly with nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV treatment, which can inadvertently inhibit POLG (McKenzie et al., 2004, Pharmaceutical Research). Beyond toxicity, the pathway is increasingly investigated as a therapeutic target in oncology, where inhibiting mtDNA replication can selectively impair the high metabolic demands of certain cancer cells (Gaspari et al., 2020). Mutations in the enzymes of this pathway, such as POLG or TWNK, lead to a spectrum of mitochondrial DNA depletion and maintenance syndromes characterized by organ failure, myopathy, and neurological decline (UniProt, 2024, P54098). Effective management of drugs interacting with this pathway requires monitoring for systemic mitochondrial dysfunction and lactic acidosis (FDA, 2023, Zidovudine Label).

Other names

Mitochondrial DNA replicationmtDNA maintenance pathwayMitochondrial replisome

Inhibition of mitochondrial DNA polymerase gamma (POLG) leading to depletion of mitochondrial DNA and disruption of oxidative phosphorylation (McKenzie et al., 2004).