Solaini Giancarlo, Sgarbi Gianluca, Baracca Alessandra
Department of Biomedical and Neuromotor Sciences, Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, via Irnerio, 48, 40126 Bologna, Italy.
Biochem Soc Trans. 2021 Apr 30;49(2):815-827. doi: 10.1042/BST20200742.
In the last two decades, IF1, the endogenous inhibitor of the mitochondrial F1Fo-ATPase (ATP synthase) has assumed greater and ever greater interest since it has been found to be overexpressed in many cancers. At present, several findings indicate that IF1 is capable of playing a central role in cancer cells by promoting metabolic reprogramming, proliferation and resistance to cell death. However, the mechanism(s) at the basis of this pro-oncogenic action of IF1 remains elusive. Here, we recall the main features of the mechanism of the action of IF1 when the ATP synthase works in reverse, and discuss the experimental evidence that support its relevance in cancer cells. In particular, a clear pro-oncogenic action of IF1 is to avoid wasting of ATP when cancer cells are exposed to anoxia or near anoxia conditions, therefore favoring cell survival and tumor growth. However, more recently, various papers have described IF1 as an inhibitor of the ATP synthase when it is working physiologically (i.e. synthethizing ATP), and therefore reprogramming cell metabolism to aerobic glycolysis. In contrast, other studies excluded IF1 as an inhibitor of ATP synthase under normoxia, providing the basis for a hot debate. This review focuses on the role of IF1 as a modulator of the ATP synthase in normoxic cancer cells with the awareness that the knowledge of the molecular action of IF1 on the ATP synthase is crucial in unravelling the molecular mechanism(s) responsible for the pro-oncogenic role of IF1 in cancer and in developing related anticancer strategies.
在过去二十年中，线粒体F1Fo - ATP合酶（ATP合酶）的内源性抑制剂IF1受到了越来越多的关注，因为人们发现它在许多癌症中过度表达。目前，多项研究结果表明，IF1能够通过促进代谢重编程、增殖以及抵抗细胞死亡，在癌细胞中发挥核心作用。然而，IF1这种促癌作用的机制仍然不明。在此，我们回顾了ATP合酶逆向工作时IF1作用机制的主要特征，并讨论了支持其在癌细胞中相关性的实验证据。特别是，IF1一个明确的促癌作用是在癌细胞暴露于缺氧或接近缺氧条件时避免ATP的浪费，从而有利于细胞存活和肿瘤生长。然而，最近有各种论文将IF1描述为ATP合酶在生理状态下（即合成ATP时）的抑制剂，因此将细胞代谢重编程为有氧糖酵解。相比之下，其他研究排除了IF1在常氧条件下作为ATP合酶抑制剂的可能性，这引发了激烈的争论。本综述聚焦于IF1作为常氧癌细胞中ATP合酶调节剂的作用，同时意识到了解IF1对ATP合酶的分子作用对于阐明IF1在癌症中促癌作用的分子机制以及制定相关抗癌策略至关重要。
