1. Biochemistry and Chemical Biology
  2. Cancer Biology
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Anti-Cancer Drugs: The mitochondrial paradox

  1. Sophie L Penman
  2. Rebecca L Jensen
  3. Robyn T Kiy
  4. Amy E Chadwick  Is a corresponding author
  1. MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom
  2. Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom
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Cite this article as: eLife 2020;9:e59140 doi: 10.7554/eLife.59140
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Figures

A structural motif in two anti-cancer drugs disrupts the production of ATP.

Mitochondria (top left) make the ATP molecules that provide cells with energy. Chains of protein complexes called electron transporters (purple; labelled I, II, III, IV and V) are embedded in the inner membrane of mitochondria. The first complex in this chain (complex I) converts NADH to NAD+ by removing an electron (middle panel), which then gets shuttled between the different complexes in the chain. This allows the complexes to actively transport protons (H+) into the space between the inner and outer membrane of the mitochondrion. The diffusion of these protons back across the inner membrane (downward black arrow) drives the enzyme that synthesizes ATP molecules. Two anti-cancer drugs, mubritinib and carboxyamidotriazole, contain a motif (top right) which inhibits complex I and consequently disrupts the production of ATP. Stephenson et al. found that inhibiting complex I in cancer cells led to reduced growth and increased death (bottom left), whereas inhibiting complex I in cardiac cells caused the cells to beat less frequently due to the reduction in ATP (bottom right).

Image credit: Sophie Penman.

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