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Comment
. 2020 Jun 25:9:e59140.
doi: 10.7554/eLife.59140.

The mitochondrial paradox

Sophie L Penman  1   2 , Rebecca L Jensen  1   2 , Robyn T Kiy  1   2 , Amy E Chadwick  1   2
Affiliations
Comment

The mitochondrial paradox

Sophie L Penman et al. Elife. .

Abstract

A structural motif that is found in two cancer drugs may be responsible for their ability to tackle cancers and for the side-effects caused by the drugs.

Keywords: anti-cancer drugs; biochemistry; cancer biology; cardiac liability; chemical biology; human; mitochondria; toxicophore.

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Conflict of interest statement

SP, RJ, RK, AC No competing interests declared

Figures

Figure 1.
Figure 1.. 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).
See this image and copyright information in PMC

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