NEET proteins belong to a highly conserved group of [2Fe–2S] proteins found across all kingdoms of life. Due to their unique [2Fe2S] cluster structure, they play a key role in the regulation of many different redox and oxidation processes. In eukaryotes, NEET proteins are localized to the mitochondria, endoplasmic reticulum (ER) and the mitochondrial-associated membranes connecting these organelles (MAM), and are involved in the control of multiple processes, ranging from autophagy and apoptosis to ferroptosis, oxidative stress, cell proliferation, redox control and iron and iron‑sulfur homeostasis. Through their different functions and interactions with key proteins such as VDAC and Bcl-2, NEET proteins coordinate different mitochondrial, MAM, ER and cytosolic processes and functions and regulate major signaling molecules such as calcium and reactive oxygen species. Owing to their central role in cells, NEET proteins are associated with numerous human maladies including cancer, metabolic diseases, diabetes, obesity, and neurodegenerative diseases. In recent years, a new and exciting role for NEET proteins was uncovered, i.e., the regulation of mitochondrial dynamics and morphology. This new role places NEET proteins at the forefront of studies into cancer and different metabolic diseases, both associated with the regulation of mitochondrial dynamics. Here we review recent studies focused on the evolution, biological role, and structure of NEET proteins, as well as discuss different studies conducted on NEET proteins function using transgenic organisms. We further discuss the different strategies used in the development of drugs that target NEET proteins, and link these with the different roles of NEET proteins in cells.

NEET蛋白质属于在所有生命王国中发现的[2Fe–2S]蛋白质高度保守的组。由于其独特的[2Fe[2S]簇结构，它们在许多不同的氧化还原和氧化过程的调节中起关键作用。在真核生物中，NEET蛋白位于线粒体，内质网（ER）和连接这些细胞器（MAM）的线粒体相关膜上，并参与多个过程的控制，从自噬和细胞凋亡到肥大症，氧化应激，细胞增殖，氧化还原控制以及铁和铁-硫稳态。通过其不同的功能和与关键蛋白（如VDAC和Bcl-2）的相互作用，NEET蛋白可协调不同的线粒体，MAM，ER和胞质过程和功能，并调节主要的信号分子（如钙和活性氧）。由于它们在细胞中的核心作用，NEET蛋白与许多人类疾病相关，包括癌症，代谢性疾病，糖尿病，肥胖症和神经退行性疾病。近年来，人们发现NEET蛋白具有令人兴奋的新作用，即线粒体动力学和形态的调节。这种新的作用将NEET蛋白置于癌症和其他代谢性疾病研究的最前沿，这两种疾病均与线粒体动力学的调控有关。在这里，我们回顾了有关NEET蛋白质的进化，生物学作用和结构的最新研究，并讨论了使用转基因生物对NEET蛋白质功能进行的不同研究。我们进一步讨论了针对NEET蛋白的药物开发中使用的不同策略，并将这些策略与NEET蛋白在细胞中的不同作用联系在一起。