DNA topoisomerase I, mitochondrial (TOP1MT) (TOP1MT)

DNA topoisomerase I, mitochondrial (TOP1MT) is a nuclear-encoded enzyme that is exclusively localized to the mitochondria, where it plays a critical role in maintaining the integrity and topology of mitochondrial DNA (mtDNA) [UniProt: Q969P6]. As a type IB topoisomerase, it functions by inducing transient single-strand breaks to relieve the torsional strain generated during mtDNA replication and transcription [PubMed: 11564820]. TOP1MT is distinct from its nuclear counterpart, TOP1, in its structure and regulatory mechanisms, lacking the large N-terminal domain found in the nuclear form, which makes it a unique target for therapeutic intervention [PubMed: 21297071]. In many cancer types, TOP1MT is upregulated to accommodate the high metabolic demands and rapid mitochondrial biogenesis of tumor cells, and its deficiency has been shown to sensitize cells to DNA-damaging agents [PubMed: 25824027]. Pharmacological inhibition of TOP1MT, often achieved through camptothecin derivatives or novel indenoisoquinolines, leads to the stabilization of TOP1MT-DNA cleavage complexes, resulting in mtDNA damage and subsequent mitochondrial-mediated apoptosis [PubMed: 27103441]. Consequently, TOP1MT is being explored as a target for developing selective inhibitors that can disrupt mitochondrial function in cancer cells while potentially minimizing nuclear genomic toxicity.

Other names

Mitochondrial DNA topoisomerase 1Topoisomerase I mitochondrialTOP1MTType IB mitochondrial topoisomerase

Stabilization of the TOP1MT-DNA covalent cleavage complex (TOP1MT-cc), which prevents DNA religation and leads to mitochondrial DNA double-strand breaks during replication, ultimately triggering apoptosis [PubMed: 27103441, PubMed: 22102362].