IF1 regulatory protein and inhibition of ATP synthase

Kaludercic and Giorgio (2016) review IF1 as a reversible inhibitor whose binding is promoted by low matrix pH and membrane potential¹. They note that its role has been studied extensively in myocardial ischemia and preconditioning, where it seems to mediate ATP synthase inhibition and so spare ATP. They add that IF1 seems to regulate the oligomeric state of the enzyme, raising cristae density and the formation of dimers². Morelli and colleagues (2019) call IF1 essential for stopping reversal of ATP synthase under uncoupled conditions, particularly in brain, which has few energy reserves⁴.

Morelli and colleagues (2019) cite a result that complicates this picture. Knocking down IF1 in HeLa cells fitted with a FRET sensor lowered cellular ATP by about a third. Cell viability and mitochondrial morphology were unaffected, which they call surprising⁴. They also cite a report that deleting the IF1-like ζ subunit from Paracoccus denitrificans has little influence on ATP hydrolysis by the synthase⁵. From this they conclude that inhibition of hydrolysis by uncoupled ATP synthase does not depend only on IF1, and that the subject needs further investigation⁵.

Kaludercic and Giorgio (2016) observe that most cancer cells are highly glycolytic and reduce ATP synthase activity, in part by overexpressing IF1¹. They argue that cancer cells depend on a delicate redox balance, since excess ROS can promote PTP opening and cell death. They speculate that IF1 and CyPD may modulate the PTP differently in cancer cells. They add that the ROS signalling triggered by IF1 overexpression in many cancer types is still unresolved³. Rottenberg (2023) cites work showing that IF1 activates the mPTP. He uses this to argue that effects Berry and colleagues reported on membrane potential in C. elegans can be attributed to mPTP activity⁷.

Spikes, Montgomery and Walker (2020) determined the structure of the dimeric bovine ATP synthase by cryo-EM. The enzyme was inhibited with residues 1 to 60 of IF1 and purified with detergents and phospholipids⁶. Rauch-Kroehnert and colleagues (2026) describe a setting where the inhibitor matters for the direction of flux. In stressed cardiomyocytes and in mitofusin-2 deficiency, ANT2 imports glycolytic ATP so that reverse synthase activity can maintain membrane potential. IF1 constrains this process to prevent ATP depletion⁸.