麻省总医院癌症中心Liron Bar-Peled课题组在研究中取得进展。他们的最新研究报道了反转录复合体的氧化控制线粒体翻译。相关论文于2025年3月26日发表在《自然》杂志上。

通过系统的碱基编辑和计算筛选，研究小组在VPS35中发现了半胱氨酸，VPS35是逆转录物转运复合体的一个成员，当突变时，它会对线粒体翻译产生表型抑制。该研究团队发现VPS35是一个反应性代谢物感应途径的基础，该途径可以降低线粒体翻译以降低ROS水平。细胞内过氧化氢氧化VPS35中的半胱氨酸残基，导致内体膜的反转录解离和随后的质膜重构。该课题组证明了逆转录底物SLC7A1的质膜定位是维持线粒体翻译所必需的。

此外，在卵巢癌模型中，VPS35水平的降低或其ROS敏感半胱氨酸的氧化使其对产生ROS的化疗（包括顺铂）产生耐药性。他们发现，细胞内ROS水平通过VPS35传递到质膜，调节线粒体翻译，将细胞质内ROS感知与线粒体ROS产生联系起来。

据介绍，活性氧（ROS）是包括癌症和神经变性在内的人类病理的基础。然而，感知ROS水平并通过其半胱氨酸残基调节其产生的蛋白质仍然不明确。

附：英文原文

Title: Oxidation of retromer complex controls mitochondrial translation

Author: Zhang, Junbing, Ali, Md Yousuf, Chong, Harrison Byron, Tien, Pei-Chieh, Woods, James, Noble, Carolina, Vornbumen, Tristan, Ordulu, Zehra, Possemato, Anthony P., Harry, Stefan, Fonticella, Jay Miguel, Fellah, Lina, Harrison, Drew, Ge, Maolin, Khandelwal, Neha, Huang, Yingfei, Chauvin, Mava, Bischof, Anica Tamara, Hambelton, Grace Marie, Gohar, Magdy Farag, Zhang, Siwen, Choi, MinGyu, Bouberhan, Sara, Oliva, Esther, Mino-Kenudson, Mari, Pavlova, Natalya N., Lawrence, Michael, Gainor, Justin F., Beausoleil, Sean A., Bardeesy, Nabeel, Mostoslavsky, Raul, Ppin, David, Ott, Christopher J., Liau, Brian, Bar-Peled, Liron

Issue&Volume: 2025-03-26

Abstract: Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.

DOI: 10.1038/s41586-025-08756-y

Source: https://www.nature.com/articles/s41586-025-08756-y