Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
Departmental Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy.
Int J Mol Sci. 2023 Aug 11;24(16):12687. doi: 10.3390/ijms241612687.
Friedreich's ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.
弗里德赖希共济失调（FRDA）是一种罕见的单基因疾病，其特征是多系统、缓慢进行性退化。由于基因中非编码区域的遗传缺陷，FRDA 细胞中 frataxin 蛋白水平严重缺乏。因此，FRDA 的病理生理学特征是与铁代谢、线粒体稳态和氧化应激相关的多种代谢紊乱。重要的是，抗氧化防御的损伤会加剧氧化损伤。这似乎与关键抗氧化蛋白的失能密切相关，如转录因子红细胞生成 2 相关因子 2（Nrf2）和线粒体超氧化物歧化酶（MnSOD）。细胞因子干扰素 γ（IFN-γ）已被证明可增加 FRDA 细胞中的 frataxin 表达，并改善 FRDA 小鼠的功能缺陷。目前，IFN-γ 作为一种潜在的治疗方法正在 FRDA 患者中进行临床评估。在这里，我们表明 IFN-γ 在不同的细胞类型中，包括 FRDA 患者来源的成纤维细胞中，迅速诱导 Nrf2 和 MnSOD 的表达。我们的数据表明，IFN-γ 通过两条独立的途径来增强 FRDA 成纤维细胞中的 Nrf2 和 MnSOD 水平。MnSOD 的表达通过早期转录调控增加，而 Nrf2 的水平则通过转录后机制诱导。我们证明，IFN-γ 处理 FRDA 成纤维细胞可通过 p21 刺激非经典 Nrf2 激活途径，并在暴露于过氧化氢时增强抗氧化反应。此外，IFN-γ 可显著降低 FRDA 成纤维细胞对过氧化氢诱导的细胞死亡的敏感性。总之，这些结果表明 IFN-γ 触发了多种具有 FRDA 治疗相关性的途径。
