Novosolova N, Braidotti N, Patinen T, Laitinen T, Ciubotaru C, Huttunen K M, Levonen A L, Cojoc D, Giniatullin R, Malm T
A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70210, Finland.
CNR Istituto Officina Dei Materiali, 34149, Trieste, Italy; Department of Physics, University of Trieste, Trieste, 34127, Italy.
Redox Biol. 2025 Jul 31;86:103797. doi: 10.1016/j.redox.2025.103797.
Emerging evidence suggests that mechanosensitive Piezo1 channels play a role in the pathomechanism of various disorders. However, the mechanisms by which accumulating pathologies regulate Piezo1 activation remain unclear. Oxidative stress, a common feature of neurodegenerative diseases, is associated with generation of reactive oxygen species (ROS). While the dependence of Piezo1 channels on temperature, pH, and voltage has been well studied, the redox regulation of these highly mechanosensitive channels remains unknown. We investigated whether oxidative stress modulates the calcium permeability of Piezo1 channels using red blood cells (RBCs) and HEK293T cells transduced with Piezo1 as model systems. Additionally, using the selective HO sensor HyPer7, we examined whether Piezo1 activation induces the generation of endogenous ROS. Using flow cytometry, Ca-imaging, patch clamp and microaspiration techniques we demonstrate that cell-permeable oxidants hydrogen peroxide (HO) and Chloramine-T, which specifically oxidize cysteines and methionines, inhibited Yoda1-induced activation of Piezo1 in both cell types. In contrast to Chloramine-T, the membrane-impermeable, cysteine-specific oxidant DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)) also inhibited Piezo1, although its inhibitory effect was less pronounced. Mechanical sensitivity of Piezo1 was reduced by HO also in RBCs. Scavenging antioxidants N-acetylcysteine and dithiothreitol decreased or eliminated the inhibitory action of HO and Chloramine-T. However, overexpression of the antioxidant transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2) did not prevent the inhibitory effects of Chloramine-T, suggesting a membrane-delimited site of redox modulation. Notably, Piezo1 activation slightly increased endogenous H2O2 production. Our data suggest that the reduced activity of Piezo1 in the oxidative environment is determined by oxidation of both cysteines and methionines, which are enriched in intracellular domains, with methionines playing a predominant role. Given the role of Piezo1 channels in pathophysiology of numerous disorders, we propose that, under conditions associated with oxidative stress, redox modulation of these mechanosensors could be a significant factor contributing to disease pathology.
新出现的证据表明，机械敏感的Piezo1通道在各种疾病的发病机制中起作用。然而，累积的病理状态调节Piezo1激活的机制仍不清楚。氧化应激是神经退行性疾病的一个常见特征，与活性氧（ROS）的产生有关。虽然Piezo1通道对温度、pH和电压的依赖性已得到充分研究，但这些高度机械敏感通道的氧化还原调节仍不清楚。我们使用转导了Piezo1的红细胞（RBC）和HEK293T细胞作为模型系统，研究氧化应激是否调节Piezo1通道的钙通透性。此外，我们使用选择性HO传感器HyPer7，检查Piezo1激活是否诱导内源性ROS的产生。使用流式细胞术、钙成像、膜片钳和微量抽吸技术，我们证明细胞可渗透的氧化剂过氧化氢（HO）和氯胺-T，它们特异性地氧化半胱氨酸和甲硫氨酸，在两种细胞类型中均抑制Yoda1诱导的Piezo1激活。与氯胺-T不同，膜不可渗透的、半胱氨酸特异性氧化剂DTNB（5,5'-二硫代双-(2-硝基苯甲酸)）也抑制Piezo1，尽管其抑制作用不太明显。HO也降低了RBC中Piezo1的机械敏感性。清除抗氧化剂N-乙酰半胱氨酸和二硫苏糖醇降低或消除了HO和氯胺-T的抑制作用。然而，抗氧化转录因子Nrf2（核因子红细胞2相关因子2）的过表达并不能阻止氯胺-T的抑制作用，这表明氧化还原调节的位点在膜上。值得注意的是，Piezo1激活略微增加了内源性H2O2的产生。我们的数据表明，在氧化环境中Piezo1活性的降低是由富含细胞内结构域的半胱氨酸和甲硫氨酸的氧化决定的，其中甲硫氨酸起主要作用。鉴于Piezo1通道在多种疾病病理生理学中的作用，我们提出，在与氧化应激相关的条件下，这些机械传感器的氧化还原调节可能是导致疾病病理的一个重要因素。
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