Visualizing mitochondrial FoF1-ATP synthase as the target of the immunomodulatory drug Bz-423

TL;DR

This paper reviews how Bz-423 targets mitochondrial FoF1-ATP synthase, revealing its binding mechanism and effects on enzyme rotation, with implications for autoimmune disease treatment.

Contribution

It demonstrates the use of FRET to visualize Bz-423 binding to mitochondrial FoF1-ATP synthase in living cells.

Findings

Bz-423 binds to subunit OSCP of FoF1-ATP synthase.

FRET can localize Bz-423 and enzyme within mitochondria.

Bz-423 affects subunit rotation of the enzyme.

Abstract

Targeting the mitochondrial enzyme FoF1-ATP synthase and modulating its catalytic activities with small molecules is a promising new approach for treatment of autoimmune diseases. The immuno-modulatory compound Bz-423 is such a drug that binds to subunit OSCP of the mitochondrial FoF1-ATP synthase and induces apoptosis via increased reactive oxygen production in coupled, actively respiring mitochondria. Here we review the experimental progress to reveal the binding of Bz-423 to the mitochondrial target and discuss how subunit rotation of FoF1-ATP synthase is affected by Bz-423. Briefly, we report how F\"orster resonance energy transfer (FRET) can be employed to colocalize the enzyme and the fluorescently tagged Bz-423 within the mitochondria of living cells with nanometer resolution.