Poisoning of mitochondrial topoisomerase I by lamellarin D.

Mol Pharmacol

Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute (S.K., K.A., I.D.R., S.A., K.F., H.Z., Y.P.) and Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute (Y.S., K.C.N.), National Institutes of Health, Bethesda, Maryland

Published: August 2014

AI Article Synopsis

  • * In experiments, Lam-D was shown to trap Top1mt and create cleavage complexes, inhibiting its ability to relax supercoils and religate, which is different from the effects of another drug, camptothecin.
  • * When tested in living cells, Lam-D quickly accumulates in mitochondria, causing damage to mitochondrial DNA, indicating its potential as a new type of therapeutic that targets mitochondrial functions by inhibiting Top1mt.

Article Abstract

Lamellarin D (Lam-D) is a hexacyclic pyrole alkaloid isolated from marine invertebrates, whose biologic 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 represents a novel strategy for targeting mitochondrial DNA.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127927PMC
http://dx.doi.org/10.1124/mol.114.092833DOI Listing

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