血红素是参与重要生理过程的蛋白质的辅基。例如，由于其中心铁原子的氧化态可变，它参与对细胞代谢至关重要的氧化还原反应。然而，过量的血红素由于其促氧化特性可能具有细胞毒性。因此，细胞内血红素水平的控制确保了生物体的生存，特别是那些在其一生中处理高浓度血红素的生物体，例如食血昆虫。最初归因于猫白血病病毒 C 受体 (FLVCR) 的血红素输出最近受到质疑，因为在哺乳动物中发现相同受体可吸收胆碱。在这里，我们发现 RpFLVCR 是食血昆虫 Rhodnius prolixus（恰加斯病的载体）中肠中的血红素输出蛋白。沉默 RpFLVCR 会降低血淋巴血红素水平，并增加细胞内双半胱氨酰胆绿素的水平，表明血红素保留在中肠细胞内。 FLVCR 沉默导致血红素加氧酶 (HO)、铁蛋白和线粒体铁蛋白 mRNA 的表达增加，同时下调铁输入者 Malvolio 1 和 2。相反，HO 基因沉默增加 FLVCR 和 Malvolio 表达并下调铁蛋白，揭示了血红素降解/输出之间的串扰和铁运输/储存途径。此外，RpFLVCR 沉默会强烈增加氧化剂的产生和脂质过氧化，降低细胞色素 c 氧化酶活性，并激活线粒体生物发生，这些效应在 RpHO 沉默的昆虫中未观察到。这些数据支持 FLVCR 作为血红素输出者的功能，在血红素/铁代谢和氧化还原平衡的维持中发挥着关键作用，特别是在适应极高浓度血红素的生物体中。© 2024 作者。 FASEB 期刊由 Wiley periodicals LLC 代表美国实验生物学学会联合会出版。

Heme is a prosthetic group of proteins involved in vital physiological processes. It participates, for example, in redox reactions crucial for cell metabolism due to the variable oxidation state of its central iron atom. However, excessive heme can be cytotoxic due to its prooxidant properties. Therefore, the control of intracellular heme levels ensures the survival of organisms, especially those that deal with high concentrations of heme during their lives, such as hematophagous insects. The export of heme initially attributed to the feline leukemia virus C receptor (FLVCR) has recently been called into question, following the discovery of choline uptake by the same receptor in mammals. Here, we found that RpFLVCR is a heme exporter in the midgut of the hematophagous insect Rhodnius prolixus, a vector for Chagas disease. Silencing RpFLVCR decreased hemolymphatic heme levels and increased the levels of intracellular dicysteinyl-biliverdin, indicating heme retention inside midgut cells. FLVCR silencing led to increased expression of heme oxygenase (HO), ferritin, and mitoferrin mRNAs while downregulating the iron importers Malvolio 1 and 2. In contrast, HO gene silencing increased FLVCR and Malvolio expression and downregulated ferritin, revealing crosstalk between heme degradation/export and iron transport/storage pathways. Furthermore, RpFLVCR silencing strongly increased oxidant production and lipid peroxidation, reduced cytochrome c oxidase activity, and activated mitochondrial biogenesis, effects not observed in RpHO-silenced insects. These data support FLVCR function as a heme exporter, playing a pivotal role in heme/iron metabolism and maintenance of redox balance, especially in an organism adapted to face extremely high concentrations of heme.© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.