Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy.
Centro di Biologia Integrata (CIBIO), Università di Trento, Trento, Italy.
Cell Biochem Funct. 2021 Jun;39(4):528-535. doi: 10.1002/cbf.3618. Epub 2021 Jan 20.
Uncontrolled oxidative stress production, especially in the outer retina is one of the causes of retinal degenerations. Mitochondria are considered the principal source of oxidative stress. However, a Reactive Oxygen Intermediates (ROI) production in the retinal photoreceptor layer seems to depend also on the expression of an extramitochondrial oxidative phosphorylation (OxPhos) machinery in the rod outer segments (OS). In fact, OS conduct aerobic metabolism, producing ATP through oxygen consumption, although it is devoid of mitochondria. As diterpenes display an antioxidant effect, we have evaluated the effect Manool, extracted from Salvia tingitana, on the extramitochondrial OxPhos and the ROI production in the retinal rod OS. Results confirm that the OxPhos machinery is ectopically expressed in the OS and that F F -ATP synthase is a target of Manool, which inhibited the OS ATP synthesis, binding the F moiety with high affinity, as analysed by molecular docking. Moreover, the overall slowdown of OxPhos metabolism reduced the ROI production elicited in the OS by light exposure, in vitro. In conclusion, data are consistent with the antioxidant properties of Salvia spp., suggesting its ability to lower oxidative stress production, a primary risk factor for degenerative retinal diseases. SIGNIFICANCE OF THE STUDY: Here we show that Manool, a diterpene extracted from Salvia tingitana has the potential to lower the free radical production by light-exposed rod outer segments in vitro, by specifically targeting the rod OS F F -ATP synthase belonging to the extramitochondrial OxPhos expressed on the disk membrane. The chosen experimental model allowed to show that the rod OS is a primary producer of oxidative stress linked to the pathogenesis of degenerative retinal diseases. Data are also consistent with the antioxidant and anti-inflammatory action of Salvia spp., suggesting a beneficial effect also in vivo.
不受控制的氧化应激产生，特别是在外视网膜，是视网膜变性的原因之一。线粒体被认为是氧化应激的主要来源。然而，视网膜光感受器层中活性氧中间体 (ROI) 的产生似乎也依赖于杆状外节 (OS) 中线粒体外氧化磷酸化 (OxPhos) 机制的表达。事实上，OS 进行需氧代谢，通过耗氧产生 ATP，尽管它没有线粒体。由于二萜类化合物具有抗氧化作用，我们评估了从 Salvia tingitana 中提取的 Manool 对 OS 中线粒体外 OxPhos 和 ROI 产生的影响。结果证实，OxPhos 机制在 OS 中异位表达，并且 F F -ATP 合酶是 Manool 的靶标，其通过高亲和力结合 F 部分抑制 OS ATP 合成，如分子对接分析所示。此外，OxPhos 代谢的整体减缓降低了体外光照下 OS 中引发的 ROI 产生。总之，数据与 Salvia spp. 的抗氧化特性一致，表明其降低氧化应激产生的能力，氧化应激产生是退行性视网膜疾病的主要风险因素。
在这里，我们表明，从 Salvia tingitana 中提取的二萜 Manool 具有通过特异性靶向位于盘膜上的杆状 OS 中的线粒体外 OxPhos 的 F F -ATP 合酶，降低体外光照下杆状外节中自由基产生的潜力。所选的实验模型表明 OS 是与退行性视网膜疾病发病机制相关的氧化应激的主要产生者。数据也与 Salvia spp. 的抗氧化和抗炎作用一致，表明其在体内也具有有益作用。
