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Review
. 2022 Aug 4:13:917203.
doi: 10.3389/fphys.2022.917203. eCollection 2022.

The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

Cristina Gatto  1 , Martina Grandi  1 , Giancarlo Solaini  1 , Alessandra Baracca  1 , Valentina Giorgio  1
Affiliations
Review

The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

Cristina Gatto et al. Front Physiol. .

Abstract

The endogenous inhibitor of ATP synthase is a protein of about 10 kDa, known as IF1 which binds to the catalytic domain of the enzyme during ATP hydrolysis. The main role of IF1 consists of limiting ATP dissipation under condition of severe oxygen deprivation or in the presence of dysfunctions of mitochondrial respiratory complexes, causing a collapse in mitochondrial membrane potential and therefore ATP hydrolysis. New roles of IF1 are emerging in the fields of cancer and neurodegeneration. Its high expression levels in tumor tissues have been associated with different roles favouring tumor formation, progression and evasion. Since discordant mechanisms of action have been proposed for IF1 in tumors, it is of the utmost importance to clarify them in the prospective of defining novel approaches for cancer therapy. Other IF1 functions, including its involvement in mitophagy, may be protective for neurodegenerative and aging-related diseases. In the present review we aim to clarify and discuss the emerging mechanisms in which IF1 is involved, providing a critical view of the discordant findings in the literature.

Keywords: ATP synthase; cancer; inhibitor protein IF1; mitochondria; neurodegeneration.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of IF1 binding to F1Fo-ATPase, favoured by acidic pH and membrane potential (Δψ) collapse.
FIGURE 2
FIGURE 2
Schematic representation of the proposed functions of IF1 in cancer. According to the literature, IF1 affects cancer development through its effects on metastasis and cristae shaping, inhibition of ATP hydrolysis and of apoptosis. A possible role has also been proposed in the modulation of both ROS level and ATP synthase during oxidative phosphorylation. The proposed mechanisms are indicated by blue arrows. The IF1 roles that are still under investigation are indicated by the dashed lines.
FIGURE 3
FIGURE 3
Multiple alignment of the amino acid sequence (residues 1–50) of human IF1 with equivalent portions of F1-ATPase inhibitor from pig, bovine, mouse proteins. The A39 residues are in light-blue in porcine and bovine, while S39 residues are grey in human and mouse sequences. The UniProt accession numbers for inhibitor proteins from Sus Scrofa, Bos taurus, Homo sapiens, Mus musculus, are shown on the left of each sequence. Asterisk (*) indicates positions which have a single, fully conserved residue; colon (:) indicates conservation between amino acid groups or similar properties.
See this image and copyright information in PMC

References

    1. Atwal K. S., Wang P., Rogers W. L., Sleph P., Monshizadegan H., Ferrara F. N., et al. (2004). Small molecule mitochondrial F 1F 0 ATPase hydrolase inhibitors as cardioprotective agents. Identification of 4-(n-Arylimidazole)-Substituted benzopyran derivatives as selective hydrolase inhibitors. J. Med. Chem. 47, 1081–1084. 10.1021/jm030291x - DOI - PubMed
    1. Bae T. J., Kim M. S., Kim J. W., Kim B. W., Choo H. J., Lee J. W., et al. (2004). Lipid Raft Proteome Reveals ATP Synthase Complex in the Cell Surface. Proteomics 4, 3536–3548. 10.1002/pmic.200400952 - DOI - PubMed
    1. Barbato S., Sgarbi G., Gorini G., Baracca A., Solaini G. (2015). The inhibitor protein (IF1) of the F1 F0-ATPase modulates human osteosarcoma cell bioenergetics. J. Biol. Chem. 290, 6338–6348. 10.1074/jbc.M114.631788 - DOI - PMC - PubMed
    1. Bason J. V., Montgomery M. G., Leslie A. G. W., Walker J. E. (2014). Pathway of Binding of the Intrinsically Disordered Mitochondrial Inhibitor Protein to F1-ATPase. Proc. Natl. Acad. Sci. U. S. A. 111, 11305–11310. 10.1073/pnas.1411560111 - DOI - PMC - PubMed
    1. Bason J. V., Runswick M. J., Fearnley I. M., Walker J. E. (2011). Binding of the Inhibitor Protein IF1 to Bovine F1-ATPase. J. Mol. Biol. 406, 443–453. 10.1016/j.jmb.2010.12.025 - DOI - PMC - PubMed

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