The inhibition of gadolinium ion (Gd3+) on the mitochondrial F1FO-ATPase is linked to the modulation of the mitochondrial permeability transition pore

The mitochondrial permeability transition pore (PTP), which drives regulated cell death when Ca2+ concentration suddenly increases in mitochondria, was related to changes in the Ca2+ -activated F1FO-ATPase. The effects of the gadolinium cation (Gd3+), widely used for diagnosis and therapy, and reported as PTP blocker, were evaluated on the F1FO-ATPase activated by Mg2+ or Ca2+ and on the PTP. Gd3+ more effectively inhibits the Ca2+-activated F1FO-ATPase than the Mg2+-activated F1FO-ATPase by a mixed-type inhibition on the former and by uncompetitive mechanism on the latter. Most likely Gd3+ binding to F-1, is favoured by Ca2+ insertion. The maximal inactivation rates (k(inact)) of pseudo-first order inactivation are similar either when the F1FO-ATPase is activated by Ca2+ or by Mg2+. The half-maximal inactivator concentrations (K-I are 2.35 +/- 0.35 mM and 0.72 +/- 0.11 mM, respectively. The potency of a mechanism-based inhibitor (k(inact)/K-I) also highlights a higher inhibition efficiency of Gd3+ on the Ca2+-activated F1FO-ATPase (0.59 +/- 0.09 mM(-1).s(-1)) than on the Mg2+ -activated F1FO-ATPase (0.13 +/- 0.02 mM(-1).s(-1)). Consistently, the PTP is desensitized in presence of Gd3+. The Gd3+ inhibition on both the mitochondrial Ca2+-activated F1FO-ATPase and the PTP strengthens the link between the PTP and the F1FO-ATPase when activated by Ca2+ and provides insights on the biological effects of Gd3+.

Automated summary

The study found that gadolinium has a strong inhibitory effect on both the mitochondrial Ca2+-activated F1FO-ATPase and the PTP, strengthening the link between the two. This provides new insights into the biological effects of Gd3+.