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线粒体抑制剂 IF1 与 ATP 合酶 OSCP 亚基结合，保护癌细胞免于凋亡。

The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis.

机构信息

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, I-40126, Italy.

Consiglio Nazionale delle Ricerche Institute of Neuroscience, Padova, I-35121, Italy.

出版信息

Cell Death Dis. 2023 Jan 23;14(1):54. doi: 10.1038/s41419-023-05572-y.

DOI:10.1038/s41419-023-05572-y
PMID:36690622
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9870916/
Abstract

The mitochondrial protein IF1 binds to the catalytic domain of the ATP synthase and inhibits ATP hydrolysis in ischemic tissues. Moreover, IF1 is overexpressed in many tumors and has been shown to act as a pro-oncogenic protein, although its mechanism of action is still debated. Here, we show that ATP5IF1 gene disruption in HeLa cells decreases colony formation in soft agar and tumor mass development in xenografts, underlining the role of IF1 in cancer. Notably, the lack of IF1 does not affect proliferation or oligomycin-sensitive mitochondrial respiration, but it sensitizes the cells to the opening of the permeability transition pore (PTP). Immunoprecipitation and proximity ligation analysis show that IF1 binds to the ATP synthase OSCP subunit in HeLa cells under oxidative phosphorylation conditions. The IF1-OSCP interaction is confirmed by NMR spectroscopy analysis of the recombinant soluble proteins. Overall, our results suggest that the IF1-OSCP interaction protects cancer cells from PTP-dependent apoptosis under normoxic conditions.

摘要

线粒体蛋白 IF1 与 ATP 合酶的催化结构域结合，并抑制缺血组织中的 ATP 水解。此外，IF1 在许多肿瘤中过度表达，并已被证明具有致癌蛋白的作用，尽管其作用机制仍存在争议。在这里，我们表明在 HeLa 细胞中敲除 ATP5IF1 基因会减少软琼脂中的集落形成和异种移植中的肿瘤质量发展，强调了 IF1 在癌症中的作用。值得注意的是，缺乏 IF1 不会影响增殖或寡霉素敏感的线粒体呼吸，但它使细胞对通透性过渡孔 (PTP) 的开放敏感。免疫沉淀和接近连接分析表明，IF1 在 HeLa 细胞中在氧化磷酸化条件下与 ATP 合酶 OSCP 亚基结合。IF1-OSCP 相互作用通过重组可溶性蛋白的 NMR 光谱分析得到证实。总的来说，我们的研究结果表明，IF1-OSCP 相互作用在常氧条件下保护癌细胞免受 PTP 依赖性细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/691acf272c8f/41419_2023_5572_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/f8db0276d2a2/41419_2023_5572_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/f92d69d71763/41419_2023_5572_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/2fdd142a406f/41419_2023_5572_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/2db427d8c944/41419_2023_5572_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/05e8800687bf/41419_2023_5572_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/16114d302168/41419_2023_5572_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/a0e345e0b781/41419_2023_5572_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/691acf272c8f/41419_2023_5572_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/f8db0276d2a2/41419_2023_5572_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/f92d69d71763/41419_2023_5572_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/2fdd142a406f/41419_2023_5572_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/2db427d8c944/41419_2023_5572_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/05e8800687bf/41419_2023_5572_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/16114d302168/41419_2023_5572_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/a0e345e0b781/41419_2023_5572_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/793b/9870916/691acf272c8f/41419_2023_5572_Fig8_HTML.jpg

相似文献

[1]
The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis.

Cell Death Dis. 2023-1-23

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[10]
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引用本文的文献

[1]
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[2]
Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Nat Commun. 2025-4-29

[3]
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Mol Biol Cell. 2025-1-1

[4]
The homolog of ATPase inhibitory factor 1 is critical for mitochondrial cristae maintenance and stress response.

bioRxiv. 2024-8-10

[5]
Mitochondrial complex-1 as a therapeutic target for cardiac diseases.

Mol Cell Biochem. 2025-2

[6]
Peptides Targeting the IF1-ATP Synthase Complex Modulate the Permeability Transition Pore in Cancer HeLa Cells.

Int J Mol Sci. 2024-4-25

[7]
Nano-flow cytometry unveils mitochondrial permeability transition process and multi-pathway cell death induction for cancer therapy.

Cell Death Discov. 2024-4-15

[8]
Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders.

Int J Mol Sci. 2024-3-18

[9]
IF1 Promotes Cellular Proliferation and Inhibits Oxidative Phosphorylation in Mouse Embryonic Fibroblasts under Normoxia and Hypoxia.

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[10]
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Int J Mol Sci. 2024-2-13

本文引用的文献

[1]
The F1Fo-ATPase inhibitor protein IF1 in pathophysiology.

Front Physiol. 2022-8-4

[2]
Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.

J Clin Invest. 2022-5-16

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Molecular mechanisms and consequences of mitochondrial permeability transition.

Nat Rev Mol Cell Biol. 2022-4

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Highly accurate protein structure prediction with AlphaFold.

Nature. 2021-8

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The f subunit of human ATP synthase is essential for normal mitochondrial morphology and permeability transition.

Cell Rep. 2021-5-11

[6]
The F1Fo-ATPase inhibitor, IF1, is a critical regulator of energy metabolism in cancer cells.

Biochem Soc Trans. 2021-4-30

[7]
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J Biochem. 2021-9-22

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Biol Chem. 2020-10-25

[9]
The spatio-temporal organization of mitochondrial FF ATP synthase in cristae depends on its activity mode.

Biochim Biophys Acta Bioenerg. 2019-11-27

[10]
Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent.

EMBO J. 2019-10-14

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