Redox Biology最新文献_第9页

Ultrasmall Cu2−xSe nanoparticles alleviate vascular calcification through inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation 超小Cu2−xSe纳米颗粒通过抑制氧化应激和NF-κB/ nlrp3介导的炎症来缓解血管钙化

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-03 DOI: 10.1016/j.redox.2025.103961

Ding Liu , Yuanzhi Ye , Zirong Lan , An Chen , Xingchen Zhou , Zhenhao Li , Xin Wen , Jisheng Xiao , Fan Ouyang , Jianyun Yan

Vascular calcification, prevalent in patients with chronic kidney disease, atherosclerosis, and diabetes, is strongly associated with elevated cardiovascular morbidity and mortality, highlighting the urgent need for effective treatments. Oxidative stress is a key contributor to the progression of vascular calcification. Nanozymes, nanomaterials with enzyme-like catalytic properties, exhibit strong reactive oxygen species (ROS) scavenging abilities and good biocompatibility, making them promising therapeutic candidates. This study aims to investigate whether polyvinylpyrrolidone (PVP)-functionalized ultrasmall Cu_2-xSe nanoparticles (CSP NPs) act as nanozymes for treating vascular calcification. In vitro, CSP NPs significantly inhibit calcification of rat and human vascular smooth muscle cells (VSMCs) and reduce the expression of osteogenic markers Runx2 and BMP2. Moreover, CSP NPs alleviate calcification of rat and human arterial rings. In a mouse model, CSP NPs localize to certain areas, such as the aortic arch and abdominal aortas, and are safely metabolized by the liver and kidneys without organ toxicity. Further analyses confirm that CSP NPs inhibit mouse and chronic kidney disease (CKD) rat aortic calcification. Mechanistically, CSP NPs inhibit oxidative stress and mitochondrial dysfunction. Additionally, CSP NPs decrease the expression of NF-κB and NLRP3, thus reducing the levels of inflammatory cytokines IL-1β and IL-6. CSP NPs suppress NLRP3 activator-induced calcification in VSMCs and arterial rings. This study provides the first evidence that CSP NPs alleviate vascular calcification by inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation, suggesting a promising therapeutic approach.

血管钙化在慢性肾脏疾病、动脉粥样硬化和糖尿病患者中普遍存在，与心血管发病率和死亡率升高密切相关，因此迫切需要有效的治疗方法。氧化应激是血管钙化进展的关键因素。纳米酶是一种具有酶样催化性能的纳米材料，具有很强的活性氧（ROS）清除能力和良好的生物相容性，是一种很有前景的治疗材料。本研究旨在探讨聚乙烯吡咯烷酮（PVP）功能化的超小Cu2-xSe纳米颗粒（CSP NPs）是否作为纳米酶治疗血管钙化。在体外实验中，CSP NPs显著抑制大鼠和人血管平滑肌细胞（VSMCs）的钙化，降低成骨标志物Runx2和BMP2的表达。此外，CSP NPs还能减轻大鼠和人动脉环的钙化。在小鼠模型中，CSP NPs定位于某些区域，如主动脉弓和腹主动脉，并被肝脏和肾脏安全代谢，无器官毒性。进一步的分析证实，CSP NPs抑制小鼠和慢性肾脏疾病（CKD）大鼠主动脉钙化。机制上，CSP NPs抑制氧化应激和线粒体功能障碍。此外，CSP NPs降低NF-κB和NLRP3的表达，从而降低炎症细胞因子IL-1β和IL-6的水平。CSP NPs抑制NLRP3激活剂诱导的VSMCs和动脉环的钙化。本研究首次证明了CSP NPs通过抑制氧化应激和NF-κB/ nlrp3介导的炎症来缓解血管钙化，提示了一种很有前景的治疗方法。

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引用次数: 0

Protic small molecule bioregulators 质子小分子生物调节剂

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103921

Amanda G. Davis, Michael D. Pluth

Small molecule gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) have long been recognized as endogenous signaling molecules with diverse physiological roles. Often described as “gasotransmitters”, these molecules complement other small molecule bioregulators (SMBs) that exert biological function across all kingdoms of life. One underappreciated distinction, however, is that many of these molecules – irrespective of whether or not they are gases in their native states outside of biology – exhibit similar molecular signaling potential mediated by protonation-dependent chemical speciation. In this review, we propose the new cross-cutting classification of protic small molecule bioregulators (PSMBs) to describe molecules in which biological function and reactivity are modulated by protonation state. Examples of PSMBs include the canonical gasotransmitter H₂S, emerging gasotransmitters (H₂Se, HCN), small molecule crosstalk species (e.g., SNO⁻, SSNO⁻, SO₄²⁻, ONOO⁻, NO₂⁻, SCN⁻, OCl⁻), and other species where protonation state modulation is accessible at physiological pH. Importantly, these species exist in equilibrium between their neutral and anionic forms, with speciation governed by local pH and molecular environment, directly impacting their membrane nucleophilicity, permeability, redox activity, and interaction with metal centers. We describe the evolutionary origins, biosynthesis, and crosstalk of PSMBs, including roles in redox signaling, post-translational modification, and mitochondrial regulation. Reframing these important molecules in a class defined by their protic ability rather than gaseous state does not diminish prior gasotransmitter designations, but rather serves to recognize commonalities in chemical characteristics that drive the unique biological chemistry and regulation of these species.

一氧化氮（NO）、一氧化碳（CO）和硫化氢（H2S）等小分子气体一直被认为是具有多种生理作用的内源性信号分子。这些分子通常被描述为“气体递质”，是对其他小分子生物调节剂（smb）的补充，这些小分子生物调节剂在所有生命领域发挥生物功能。然而，一个被低估的区别是，这些分子中的许多——不管它们在生物学之外是否是天然状态的气体——都表现出类似的由质子依赖的化学物种形成介导的分子信号传导潜力。在这篇综述中，我们提出了新的质子小分子生物调节剂（PSMBs）的交叉分类，以描述生物功能和反应性受质子化状态调节的分子。PSMBs的例子包括典型的气体递质H2S，新兴的气体递质（H2Se， HCN），小分子串扰物种（例如，SNO -, SSNO -, SO42 -, ONOO -, NO2 -, SCN -, OCl -），以及其他在生理pH下可以进行质子化状态调节的物种。重要的是，这些物种存在于中性和阴离子形式之间的平衡状态，物种形成受局部pH和分子环境的控制，直接影响它们的膜亲核性，渗透性，渗透性，渗透性，渗透性，渗透性，渗透性，渗透性，渗透性和渗透性。氧化还原活性，以及与金属中心的相互作用。我们描述了PSMBs的进化起源、生物合成和串扰，包括在氧化还原信号、翻译后修饰和线粒体调节中的作用。将这些重要的分子按其质子能力而不是气态来定义，并不会减少先前的气体传递器名称，而是有助于认识化学特征的共性，这些共性驱动了这些物种独特的生物化学和调节。

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引用次数: 0

Melatonin attenuates atherosclerotic plaque vulnerability through SIRT6-dependent regulation of vascular smooth muscle cells senescence 褪黑素通过sirt6依赖性调节血管平滑肌细胞衰老，减轻动脉粥样硬化斑块易损性

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103939

Yue Wang , Wenxin Zhao , Leli Zhang , Pengrong Guo , Yi Zou , Zhenbai Qin , Yuan Wang , Xiaofan Wu

Rupture of vulnerable atherosclerotic plaques is a major cause of acute cardiovascular events. Vascular smooth muscle cell (VSMC) senescence promotes plaque vulnerability by impairing fibrous cap integrity. Although melatonin exhibits atheroprotective potential, its capacity to stabilize plaques by targeting VSMC senescence along with the underlying mechanisms, remains unclear. In this study, a vulnerable plaque model was established in ApoE^−/− mice by partial ligation of the left carotid artery combined with a high-fat diet. Melatonin treatment substantially enhanced plaque stability, as indicated by decreased plaque burden, increased fibrous cap thickness, and an elevated collagen-to-lipid ratio. These effects were prevented by the MT membrane receptor antagonist luzindole. Melatonin markedly suppressed VSMC senescence in both plaques and hydrogen peroxide-stimulated VSMCs; this suppression was similarly abolished by luzindole. Transcriptomic analysis identified SIRT6 as the most significantly upregulated sirtuin in response to melatonin treatment. Melatonin upregulated SIRT6 expression in a MT membrane receptor-dependent manner. Notably, VSMC-specific SIRT6 knockdown eliminated the beneficial effects of melatonin on plaque stabilization and VSMC senescence attenuation. Mechanistically, melatonin alleviated oxidative stress by activating the Nrf2 antioxidant pathway-an effect nullified by SIRT6 knockdown or inhibition. This study uncovers a novel mechanism by which melatonin mitigates atherosclerotic plaque vulnerability through inhibition of VSMC senescence. This protective action is mediated via MT membrane receptor-dependent activation of the SIRT6/Nrf2 signaling axis, culminating in reduced oxidative stress.

易损动脉粥样硬化斑块破裂是急性心血管事件的主要原因。血管平滑肌细胞（VSMC）衰老通过损害纤维帽完整性促进斑块易感性。尽管褪黑素具有保护动脉粥样硬化的潜力，但其通过靶向VSMC衰老来稳定斑块的能力及其潜在机制尚不清楚。在这项研究中，通过部分结扎左颈动脉结合高脂肪饮食，在ApoE−/−小鼠中建立了易损斑块模型。褪黑素治疗显著增强了斑块的稳定性，如减少斑块负担、增加纤维帽厚度和提高胶原/脂质比率所示。这些作用被MT膜受体拮抗剂卢津多所阻止。褪黑素显著抑制斑块和过氧化氢刺激的VSMC衰老；这种抑制作用同样被卢津多所消除。转录组学分析发现SIRT6是对褪黑激素治疗反应中最显著上调的sirtuin。褪黑素以MT膜受体依赖的方式上调SIRT6的表达。值得注意的是，VSMC特异性SIRT6敲低消除了褪黑素对斑块稳定和VSMC衰老衰减的有益作用。从机制上讲，褪黑激素通过激活Nrf2抗氧化途径减轻氧化应激，这一作用被SIRT6敲低或抑制所抵消。本研究揭示了褪黑素通过抑制VSMC衰老来减轻动脉粥样硬化斑块易损性的新机制。这种保护作用是通过MT膜受体依赖的SIRT6/Nrf2信号轴的激活介导的，最终减少氧化应激。

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引用次数: 0

Endogenous mitochondrial hydrogen peroxide regulates neurogenesis during cortical development 内源性线粒体过氧化氢调节皮层发育过程中的神经发生

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103940

Regina Mengual , Verónica Bobo-Jiménez , Cristina Rodríguez , Rebeca Lapresa , Darío García-Rodríguez , Daniel Jiménez-Blasco , Elisa Cabiscol , Joaquim Ros , María Delgado-Esteban , Juan P. Bolaños , Ángeles Almeida

Reactive oxygen species (ROS), particularly superoxide anion (O₂^•-) and hydrogen peroxide (H₂O₂), originating from mitochondria, are increasingly recognized as critical mediators of physiological signaling and cellular function. While in the adult brain, mitochondrial ROS, specifically mitochondrial H₂O₂, modulate metabolism and sustains cognitive processes, their role in the developing cerebral cortex remains undefined. Here, we leverage a knock-in mouse model constitutively expressing mitochondrially targeted catalase (mCAT) to attenuate mitochondrial H₂O₂ levels and investigate their impact during cortical development. In neurosphere cultures derived from embryonic day 14.5 (E14.5) mCAT mice, reduced mitochondrial H₂O₂ altered glutathione redox homeostasis and glucose metabolism leading to suppressed progenitor cell proliferation, without compromising viability. In vivo, neural progenitor cell (NPC) proliferation, neuronal differentiation and cortical layering were disrupted starting at gestational day E15. Together, these data uncover a physiological role for mitochondrial hydrogen peroxide in orchestrating neural precursor proliferation and differentiation, ultimately influencing mammalian cerebral cortex formation.

活性氧（ROS），特别是超氧阴离子（O2•-）和过氧化氢（H2O2），起源于线粒体，越来越被认为是生理信号传导和细胞功能的重要介质。虽然在成人大脑中，线粒体ROS，特别是线粒体H2O2，调节代谢并维持认知过程，但它们在发育中的大脑皮层中的作用尚不清楚。在这里，我们利用敲入小鼠模型组成表达线粒体靶向过氧化氢酶（mCAT）来减弱线粒体H2O2水平，并研究它们在皮质发育过程中的影响。在胚胎14.5天（E14.5） mCAT小鼠的神经球培养物中，线粒体H2O2的减少改变了谷胱甘肽氧化还原稳态和葡萄糖代谢，导致祖细胞增殖受到抑制，但不影响生存能力。在体内，神经祖细胞（NPC）增殖、神经元分化和皮层分层从妊娠第15天开始中断。总之，这些数据揭示了线粒体过氧化氢在协调神经前体增殖和分化中的生理作用，最终影响哺乳动物大脑皮层的形成。

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引用次数: 0

A near-infrared fluorescent probe for dynamic HClO monitoring in epilepsy and high-throughput discovery of natural neuroprotectants 近红外荧光探针用于癫痫患者动态hcl监测和高通量天然神经保护剂的发现

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103946

Qiuyan Yin , Congzhe Hou , Deyun Zhang , Mengru Li , Mingshi Zhang , Tong Ye , Yanxue Shi , Zhibo Gai , Baoguo Li , Bin Yan

Epilepsy is a neurodegenerative disease closely associated with mitochondrial oxidative stress and neuronal damage, posing a grave threat to human health. Hypochlorous acid (HClO), a potent oxidant, has been demonstrated to play a critical role in the occurrence and progression of epilepsy. Accordingly, the development of a mitochondrial-targeted responsive HClO fluorescent probe could serve as a powerful tool for the early diagnosis of epilepsy and high-throughput screening (HTS) of natural neuroprotective. Herein, we report a mitochondria-targeted fluorescent probe (MB-Mito) with excellent selectivity, rapid activation kinetics, and blood-brain barrier (BBB) permeability, which is used for real-time and in situ tracking of HClO fluctuations in epilepsy models. More significantly, a visual HTS platform for natural neuroprotective agents was established based on MB-Mito, and an effective neuroprotective agent, myricetin, was identified from 47 natural compounds with potential antioxidant activity. Mechanistic studies have demonstrated that myricetin activates the ERK/Nrf2/HO-1 signaling pathway to mitigate mitochondrial oxidative stress, thereby providing precise treatment for epilepsy. All studies have confirmed that MB-Mito is a reliable tool for precise monitoring of HClO, drug HTS and mechanism research, promoting advances in the diagnosis and treatment of epilepsy.

癫痫是一种与线粒体氧化应激和神经元损伤密切相关的神经退行性疾病，对人类健康构成严重威胁。次氯酸（HClO）是一种强氧化剂，已被证明在癫痫的发生和发展中起关键作用。因此，线粒体靶向反应性HClO荧光探针的开发可作为癫痫早期诊断和天然神经保护物质高通量筛选（HTS）的有力工具。在此，我们报道了一种线粒体靶向荧光探针（MB-Mito），它具有出色的选择性、快速的激活动力学和血脑屏障（BBB）的通透性，可用于实时和原位跟踪癫痫模型中的HClO波动。更重要的是，基于MB-Mito建立了天然神经保护剂的可视化HTS平台，并从47种具有潜在抗氧化活性的天然化合物中鉴定出有效的神经保护剂杨梅素。机制研究表明，杨梅素激活ERK/Nrf2/HO-1信号通路，减轻线粒体氧化应激，从而为癫痫提供精确治疗。所有研究都证实MB-Mito是HClO精确监测、药物HTS和机制研究的可靠工具，促进了癫痫诊断和治疗的进步。

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引用次数: 0

MAOB promotes ROS-mediated DNA damage, triggering a cyclic MAOB-HNF1A-53BP1-p53 axis that suppresses the malignancy of clear cell renal cell carcinoma MAOB促进ros介导的DNA损伤，触发循环MAOB- hnf1a - 53bp1 -p53轴，抑制透明细胞肾细胞癌的恶性

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103945

Kuo-Hao Ho , Yung-Wei Lin , Hsiang-Ching Huang , Feng-Ru Lai , Yi-Chieh Yang , Chung-Howe Lai , Yu-Ching Wen , Feng-Koo Hsieh , Wei-Jiunn Lee , Ming-Hsien Chien

Monoamine oxidases (MAOA and MAOB) are mitochondrial enzymes that degrade various monoamine neurotransmitters, which have been recognized as important regulators of tumor progression. Recently, conflicting roles of both enzymes were identified in several cancer types. However, their potential involvement in the progression of clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, in silico analysis of the TCGA-KIRC dataset revealed that MAOB has a more significant prognostic impact than MAOA and serves as an independent prognostic factor for overall survival in ccRCC. Lower MAOB transcript and protein levels were observed in RCC tissues compared to normal tissues and were associated with larger tumor sizes. Enzymatically active MAOB promoted reactive oxygen species (ROS)-induced DNA damage, subsequently enhancing the stability and transcriptional activity of p53, which induced G1 cell cycle arrest, mitochondria apoptosis, and lipid peroxidation-triggered ferroptosis, ultimately suppressing tumor growth both in vitro and in vivo. Molecular studies showed that MAOB stabilizes and activates p53 through post-translational modifications (PTMs), including increased phosphorylation at Ser15 and acetylation at Lys382, as well as activation of the hepatocyte nuclear factor 1 homeobox A (HNF1A)–p53-binding protein 1 (53BP1) axis. Activated p53, in turn, regulated MAOB through positive feedback. Clinically, ccRCC samples revealed a positive correlation between MAOB and HNF1A expression, with patients expressing high levels of both having the best prognoses. Regarding therapeutic aspects, we discovered that DNA methyltransferase inhibitors serve as potential MAOB inducer in ccRCC. The current findings reveal novel mechanisms by which MAOB suppresses the malignancy of ccRCC and suggest that MAOB may serve as a valuable prognostic marker in the management of ccRCC.

单胺氧化酶（MAOA和MAOB）是线粒体酶，降解各种单胺类神经递质，已被认为是肿瘤进展的重要调节因子。最近，这两种酶在几种癌症类型中发现了相互冲突的作用。然而，它们在透明细胞肾细胞癌（ccRCC）进展中的潜在参与尚不清楚。在本研究中，TCGA-KIRC数据集的计算机分析显示，MAOB比MAOA具有更显著的预后影响，并且是ccRCC总生存的独立预后因素。与正常组织相比，在RCC组织中观察到较低的MAOB转录物和蛋白质水平，并且与较大的肿瘤大小有关。具有酶活性的MAOB促进活性氧（ROS）诱导的DNA损伤，进而增强p53的稳定性和转录活性，从而诱导G1细胞周期阻滞、线粒体凋亡和脂质过氧化引发的铁凋亡，最终在体外和体内抑制肿瘤生长。分子研究表明，MAOB通过翻译后修饰（PTMs）稳定和激活p53，包括增加Ser15位点磷酸化和Lys382位点乙酰化，以及激活肝细胞核因子1同源盒A (HNF1A) - p53结合蛋白1 （53BP1）轴。激活的p53反过来通过正反馈调节MAOB。临床上，ccRCC样本显示MAOB和HNF1A表达呈正相关，两者表达水平高的患者预后最好。在治疗方面，我们发现DNA甲基转移酶抑制剂在ccRCC中作为潜在的MAOB诱导剂。目前的研究结果揭示了MAOB抑制ccRCC恶性肿瘤的新机制，并提示MAOB可能作为ccRCC治疗中有价值的预后标志物。

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引用次数: 0

Beyond molecular chaperoning: AHA1 reprograms autophagy flux through direct ATP5A1 interaction in ischemic neuronal injury 在缺血性神经元损伤中，AHA1通过ATP5A1的直接相互作用重编程自噬通量

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103920

Duo Jin , Xinran Ge , Li Liu , Yujie Jia , Chang Liu , Ke Meng , Xiaowei Zhang

Background

Mitochondrial dysfunction and excessive reactive oxygen species (ROS) generation play a pivotal role in ischemic neuronal injury. The Activator of 90kDa heat shock protein ATPase homolog 1 (AHSA1/AHA1) has been implicated in regulating ATP synthesis and energy metabolism. Yet, its role in neurological functional impairment and mitophagy under pathological conditions remains unclear.

Methods

We utilized in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) neuronal cell models. The study integrated bioinformatics, molecular biology techniques, histological analyses, behavioral tests, and genetic knockdown (siRNA) to elucidate the underlying mechanisms.

Results

Our findings demonstrate that I/R stress induces the transcription factor STAT3 to upregulate AHA1 expression. AHA1 then translocates to the mitochondria and directly interacts with the ATP synthase subunit ATP5A1. This interaction disrupts the cellular ATP/AMP ratio and increases ROS production, leading to mitochondrial damage. The resulting energy stress triggers the aberrant activation of the AMPK/mTOR/ULK1 signaling pathway, culminating in an excessive and detrimental flux of PINK1/Parkin-mediated mitophagy. Critically, silencing of AHA1 reversed these effects, suppressing pathological mitophagy, reducing infarct volume, and improving neurological outcomes.

Conclusion

This study reveals a novel, non-canonical function for AHA1 as a pathological driver in ischemic stroke. By directly interacting with ATP5A1, AHA1 links transcriptional stress responses to mitochondrial bioenergetic failure and excessive autophagy. Targeting the AHA1-ATP5A1 axis represents a promising therapeutic strategy to inhibit maladaptive mitophagy and protect against neurological outcomes.

线粒体功能障碍和过量活性氧（ROS）的产生在缺血性神经元损伤中起关键作用。90kDa热休克蛋白ATP酶同源物激活因子1 （AHSA1/AHA1）参与调节ATP合成和能量代谢。然而，其在病理条件下神经功能损伤和有丝分裂中的作用尚不清楚。方法采用大脑中动脉闭塞/再灌注（MCAO/R）小鼠体内模型和体外氧糖剥夺/再灌注（OGD/R）神经元细胞模型。该研究综合了生物信息学、分子生物学技术、组织学分析、行为测试和基因敲低（siRNA）来阐明潜在的机制。结果I/R应激可诱导转录因子STAT3上调AHA1的表达。然后AHA1易位到线粒体并直接与ATP合成酶亚基ATP5A1相互作用。这种相互作用破坏了细胞ATP/AMP的比例，增加了ROS的产生，导致线粒体损伤。由此产生的能量应激触发AMPK/mTOR/ULK1信号通路的异常激活，最终导致PINK1/帕金森介导的有丝分裂过度和有害的通量。关键的是，AHA1的沉默逆转了这些作用，抑制病理性有丝分裂，减少梗死面积，改善神经预后。结论：本研究揭示了AHA1在缺血性脑卒中中作为病理驱动因子的一种新的非典型功能。通过直接与ATP5A1相互作用，AHA1将转录应激反应与线粒体生物能量衰竭和过度自噬联系起来。靶向AHA1-ATP5A1轴是一种很有前途的治疗策略，可以抑制适应性不良的线粒体自噬，并保护神经系统免受影响。

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引用次数: 0

Corrigendum to “DAPL1 deficiency in mice impairs antioxidant defenses in the RPE and leads to retinal degeneration with AMD-like features” [Red. Biol. 62 (2023) 102675] “小鼠DAPL1缺乏损害RPE的抗氧化防御并导致具有amd样特征的视网膜变性”[红色]的更正。生物学报，62 (2023)102675]

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103938

Xiaoyin Ma , Huaicheng Chen , Shuhui Jian , Junhao He , Youjia Liu , Shuxian Han , Lifu Chang , Pingping Li , Ying-ao Chen , Xiaoyan Liu , Xiaojuan Hu , Yu Chen , Ling Hou

引用次数: 0

NADPH oxidase isoform NOX-2 deficiency affects mitochondrial oxygen consumption and metabolic flexibility NADPH氧化酶异构体NOX-2缺乏影响线粒体耗氧量和代谢灵活性

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103948

Kannathasan Thetchinamoorthy , Diana Wierzbicka , Emilia Waraksa-Zasada , Michalina Kazek , Adrian Konopko , Mariusz Z. Ratajczak , Magdalena Kucia

Our recent study showed that the intracellular pattern recognition receptor Nlrp3 inflammasome, activated by reactive oxygen species (ROS), regulates metabolism in hematopoietic cells by maintaining proper “tonic activation” of the electron transport chain (ETC) in mitochondria. Therefore, we asked whether a deficiency in the expression of NADPH oxidase isoform NOX-2, a primary source of ROS in hematopoietic cells, would similarly affect mitochondrial function and metabolic adaptation to stress. In this study, we examined how NOX-2 influences ETC, redox balance, and glycolytic adaptation in lineage-negative Sca-1⁺c-Kit⁺ (SKL) bone marrow stem cells from wild-type (WT) and NOX-2 knockout (NOX2-KO) mice. Metabolic testing revealed that NOX2-KO cells have impaired mitochondrial respiration, lower ATP production, and reduced spare respiratory capacity. When exposed to hydrogen peroxide, NOX2-KO cells failed to activate a mitochondrial stress response and instead relied more on anaerobic glycolysis. Treatment with extracellular ATP (eATP), the most abundant signaling alarmin, increased ROS levels in WT cells but not in NOX2-KO cells, emphasizing eATP-NOX-2's role in redox regulation during stress conditions. Proteomic analysis identified proteins differentially expressed related to hypoxia, glycolysis, and oxidative stress response between WT and NOX2-KO SKL cells. These results demonstrate NOX-2 as a key regulator of mitochondrial function and metabolic flexibility in hematopoietic stem cells, highlighting its importance in maintaining redox balance during stress conditions.

我们最近的研究表明，细胞内模式识别受体Nlrp3炎性体在活性氧（ROS）的激活下，通过维持线粒体中电子传递链（ETC）的适当“强直激活”来调节造血细胞的代谢。因此，我们想知道NADPH氧化酶异构体NOX-2（造血细胞中ROS的主要来源）的表达缺乏是否会同样影响线粒体功能和对应激的代谢适应。在这项研究中，我们研究了NOX-2如何影响来自野生型（WT）和NOX-2敲除（NOX2-KO）小鼠的谱系阴性Sca-1+c-Kit+ (SKL)骨髓干细胞的ETC、氧化还原平衡和糖酵解适应。代谢测试显示NOX2-KO细胞线粒体呼吸受损，ATP产生降低，备用呼吸能力降低。当暴露于过氧化氢时，NOX2-KO细胞不能激活线粒体应激反应，而是更多地依赖于厌氧糖酵解。细胞外ATP （eATP）是最丰富的信号报警蛋白，在WT细胞中增加了ROS水平，而在NOX2-KO细胞中没有，强调了应激条件下eATP- nox -2在氧化还原调节中的作用。蛋白质组学分析鉴定出WT和NOX2-KO SKL细胞中与缺氧、糖酵解和氧化应激反应相关的蛋白差异表达。这些结果表明，NOX-2是造血干细胞线粒体功能和代谢灵活性的关键调节因子，突出了其在应激条件下维持氧化还原平衡的重要性。

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引用次数: 0

The Rieske iron-sulfur protein is a primary target of molecular hydrogen Rieske铁硫蛋白是氢分子的主要目标

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology

Pub Date : 2025-12-01 DOI: 10.1016/j.redox.2025.103952

Shuto Negishi , Mikako Ito , Tomoya Hasegawa , Hikaru Otake , Bisei Ohkawara , Akio Masuda , Hiroyuki Mino , Tyler W. LeBaron , Kinji Ohno

The mechanisms underlying the biomedical effects of molecular hydrogen (H₂) remain poorly understood and are often attributed to its selective reduction of hydroxyl radicals, based on the long-held notion that H₂ is biologically inert. We demonstrate that H₂ is biologically active, specifically targeting the Rieske iron-sulfur protein (RISP). We first observed that H₂ induces the mitochondrial unfolded protein response (UPR^mt) in cultured cells exposed to H₂ and in mouse liver after H₂ water administration. H₂ suppressed electron transport chain complex III activity in mouse liver homogenates to 78.5 % within 2 min. Given the evolutionary link with hydrogenases, we examined RISP as a potential target of H₂. We found that H₂ promotes RISP degradation within 1 h in cultured cells by activating mitochondrial Lon peptidase 1 (LONP1). Loss of RISP and subsequent UPR^mt induction may explain the pleiotropic and paradoxical effects of H₂. These findings identify RISP as a primary target of H₂, demonstrating that H₂ is biologically active as a signaling molecule.

分子氢（H2）的生物医学作用机制仍然知之甚少，通常归因于其选择性还原羟基自由基，基于H2是生物惰性的长期观念。我们证明H2具有生物活性，特别是针对Rieske铁硫蛋白（RISP）。我们首先观察到H2在暴露于H2的培养细胞和H2水处理后小鼠肝脏中诱导线粒体未折叠蛋白反应（UPRmt）。H2在2分钟内抑制小鼠肝脏匀浆中电子传递链复合物III的活性至78.5%。考虑到与氢化酶的进化联系，我们研究了RISP作为H2的潜在靶标。我们发现H2通过激活线粒体Lon肽酶1 (LONP1)，在培养细胞1小时内促进RISP降解。RISP的丢失和随后的UPRmt诱导可以解释H2的多效性和矛盾效应。这些发现确定了RISP是H2的主要靶标，表明H2作为一种信号分子具有生物活性。

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