PT  - JOURNAL ARTICLE
AU  - Salim Khiati
AU  - Yeonee Seol
AU  - Keli Agama
AU  - Ilaria Dalla Rosa
AU  - Surbhi Agrawal
AU  - katherine Fesen
AU  - Hongliang Zhang
AU  - Keir Neuman
AU  - Yves Pommier
TI  - Poisoning of Mitochondrial Topoisomerase I by Lamellarin D
AID  - 10.1124/mol.114.092833
DP  - 2014 Jan 01
TA  - Molecular Pharmacology
PG  - mol.114.092833
4099  - http://molpharm.aspetjournals.org/content/early/2014/06/02/mol.114.092833.1.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/06/02/mol.114.092833.1.full
AB  - Lamellarin D (Lam-D) is a hexacyclic pyrole alkaloid isolated from marine invertebrates whose biological properties have been attributed to mitochondrial targeting. Mitochondria contain their own DNA (mtDNA), and the only specific mitochondrial topoisomerase in vertebrates is mitochondrial topoisomerase I (Top1mt). Here, we show that Top1mt is a direct mitochondrial target of Lam-D. In vitro Lam-D traps Top1mt and induces Top1mt cleavage complexes (Top1mtcc). Using single molecule analyses we also show that Lam-D slows down supercoil relaxation of Top1mt and strongly inhibits Top1mt religation in contrast to the inefficacy of camptothecin on Top1mt. In living cells, we show that Lam-D accumulates rapidly inside mitochondria, induces cellular Top1mtcc and leads to mtDNA damage. This study provides evidence that Top1mt is a direct mitochondrial target of Lam-D and suggests that developing Top1mt inhibitors represent a novel strategy for targeting mitochondrial DNA.