Mitochondrial Ca²⁺‐activated F₁F_O‐ATPase hydrolyzes ATP and promotes the permeability transition pore

Abstract

The properties of the mitochondrial F1FO‐ATPase catalytic site, which can bind Mg2+, Mn2+, or Ca2+ and hydrolyze ATP, were explored by inhibition kinetic analyses to cast light on the Ca2+‐activated F1FO‐ATPase connection with the permeability transition pore (PTP) that initiates cascade events leading to cell death. While the natural cofactor Mg2+ activates the F1FO‐ATPase in competition with Mn2+, Ca2+ is a noncompetitive inhibitor in the presence of Mg2+. Selective F1 inhibitors (Is‐F1), namely NBD‐Cl, piceatannol, resveratrol, and quercetin, exerted different mechanisms (mixed and uncompetitive inhibition) on either Ca2+‐ or Mg2+‐activated F1FO‐ATPase, consistent with the conclusion that the catalytic mechanism changes when Mg2+ is replaced by Ca2+. In a partially purified F1 domain preparation, Ca2+‐activated F1‐ATPase maintained Is‐F1 sensitivity, and enzyme inhibition was accompanied by the maintenance of the mitochondrial calcium retention capacity and membrane potential. The data strengthen the structural relationship between Ca2+‐activated F1FO‐ATPase and the PTP, and, in turn, on consequences, such as physiopathological cellular changes.

Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction

“…Resveratrol prevents ventricular hypertrophy (Chelladurai et al, 2019) and cardiac remodeling following chronic kidney disease (Li et al, 2020a). Resveratrol also helps to protect aortic valve stenosis (Samiei et al, 2019), septic cardiomyopathy (Liang et al, 2019), diabetic cardiomyopathy (Hoseini et al, 2019), and heart failure (Algieri et al, 2019). Most associated studies have focused on the influence of resveratrol on hyperlipemia-related cardiomyocyte damage or metabolic reprogramming, but not on high-fat-related endothelial dysfunction.…”

“…Mitochondrial biogenesis is partly enhanced by resveratrol through the miR-22/Sirt1 signaling pathway (Mao et al, 2019). Mitochondrial calcium homeostasis and mitochondrial potential stabilization are also under the control of resveratrol (Algieri et al, 2019). Mitochondrial morphological alterations, such as mitochondrial fission and fusion, are also balanced by resveratrol in different types of cells, such as hepatocytes (Chen et al, 2019b), cardiomyocytes (Lu et al, 2019), and endothelium (Yu et al, 2019).…”

1,5‐Disubstituted‐1,2,3‐triazoles as inhibitors of the mitochondrial Ca2+‐activated F1FO‐ATP(hydrol)ase and the permeability transition pore

“…5A and C). Most likely, the different effect on the two differently activated F 1 F O ‐ATPases depends on the enzyme conformations promoted by the cofactor(s) bound to the catalytic and/or noncatalytic sites of the F 1 domain 10,12,30 . The capability of different divalent cations to drive the F 1 –ATPase mechanochemical coupling in mitochondria from different biological sources remains to be ascertained.…”

“…However, this bifunctional activity, unique in nature, is only sustained by the natural cofactor Mg 2+ , 9 while the substitution of Mg 2+ by Ca 2+ only allows oligomycin‐sensitive ATP hydrolysis, namely, the coupling between F 1 and F O 10 . The abrupt increase in matrix Ca 2+ concentration associated with oxidative stress under physio‐pathological conditions activates the F 1 F O ‐ATPase catalytic site, hydrolyzes CaATP, and triggers mPTP formation 11,12 . These features make the Ca 2+ ‐activated F 1 F O ‐ATPase an intriguing therapeutic target 13 .…”

The mitochondrial permeability transition pore in cell death: A promising drug binding bioarchitecture

“…The conformational change in F 1 would be transmitted to the nearby OSCP subunit and through the peripheral stalk, reach the IMM where the mPTP opens . Consistently, the aim is to discover new drugs that selectively prevent Ca 2+ binding to the catalytic sites of F 1 domain thus evading the mPTP formation . On the other hand, the extreme refractoriness to death of cancer cells suggests that these cells have evolved mechanisms to escape mPTP opening by desensitizing the mPTP to mPTP regulators.…”