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Circulating Neuregulin-4 tracks acute hyperbaric and workload stress in human divers, preceding oxidative injury markers. 循环神经调节蛋白-4跟踪人类潜水员的急性高压和工作负荷压力,在氧化损伤标志物之前。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1016/j.freeradbiomed.2026.02.002
Claudia Di Biagio, Paola Giglio, Matteo Bordi, Giovanni Larotondo, Riccardo Turchi, Luigi Fattorini, Enrico Marchetti, Daniele Lettieri-Barbato, Costanza Montagna, Giuseppe Filomeni, Katia Aquilano

Acute hyperbaric stress during diving combines increased ambient pressure, hyperoxia, hemodynamic shifts, and often muscular workload. Identifying real-time blood biomarkers sensitive to these individual and combined physiological loads remains a challenge. Neuregulin-4 (NRG4), an adipokine secreted by thermogenic and subcutaneous white fat, responds to adrenergic stimulation and modulates redox homeostasis. We investigated NRG4 dynamics alongside oxidative protein carbonyls in divers in warm (thermoneutral) water (∼33.6 °C ambient water temperature) to avoid cold stress. Two field campaigns were conducted: a first depth response campaign involved divers exposed to 20, 30, or 40 m on separate days, without exercise, with serial blood sampling; a second physical effort study involved 15 m dives with or without slow-pedalling exercise. Serum NRG4 was quantified by ELISA and expressed as log2 fold change relative to baseline. Protein carbonyls were measured as markers of oxidative damage. Statistical analysis employed single-sample tests and false-discovery rate control. NRG4 exhibited a robust early increase at 30 m, significant after correction, and nominal elevations at 40 m, but remained unchanged at 20 m. Exercise at 15 m triggered a significant early NRG4 rise absent during passive dives at the same depth. Protein carbonyls remained stable in early post-emersion windows but increased significantly at later time points (180- and 240-min post-emersion) following dives to 40 m, indicating delayed oxidative burden. Our findings position NRG4 as a fast, pressure- and workload-responsive biomarker of diving stress, temporally distinct from classical oxidative injury markers that manifest later. This temporal dissociation underscores the potential of NRG4 for real-time monitoring of acute physiological load during hyperbaric exposure, integrating pressure- and workload-related stressors.

潜水时的急性高压应激包括环境压力增加、高氧、血流动力学变化和肌肉负荷。识别对这些个体和组合生理负荷敏感的实时血液生物标志物仍然是一个挑战。神经调节蛋白-4 (NRG4)是一种由热源性和皮下白色脂肪分泌的脂肪因子,可响应肾上腺素能刺激并调节氧化还原稳态。我们研究了潜水员在温暖(热中性)水中(环境水温约33.6°C)中NRG4和氧化蛋白羰基的动态变化,以避免冷应激。进行了两次现场活动:第一次深度反应活动涉及潜水员在不同的天暴露于20,30或40米,没有运动,并进行连续血液采样;第二项体力消耗研究涉及15米跳水,有或没有慢速蹬车锻炼。采用ELISA定量测定血清NRG4,表达量为相对于基线的log2倍变化。测定蛋白质羰基作为氧化损伤的标志物。统计分析采用单样本测试和错误发现率控制。NRG4在30 m处表现出强劲的早期上升,校正后显著,在40 m处名义海拔上升,但在20 m处保持不变。在15米深度的运动触发了显著的早期NRG4上升,而在相同深度的被动潜水中则没有。蛋白质羰基在早期恢复窗口保持稳定,但在潜水至40米后的较晚时间点(恢复后180和240分钟)显著增加,表明氧化负担延迟。我们的研究结果表明,NRG4是一种快速、压力和工作负荷响应的潜水应激生物标志物,与传统的氧化损伤标志物在时间上有所不同。这种时间分离强调了NRG4在高压暴露期间实时监测急性生理负荷、整合压力和工作负荷相关应激源方面的潜力。
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引用次数: 0
Distinct quaternary reaction behavior and stable charge-transfer complex formation in Schistosoma mansoni sulfide:quinone oxidoreductase. 曼氏血吸虫硫化物醌氧化还原酶中独特的季反应行为和稳定的电荷转移复合物形成。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1016/j.freeradbiomed.2026.01.063
Augustin Tshibaka Kabongo, Talaam Keith Kiplangat, Yuki Tayama, Acharjee Rajib, Yuichi Matsuo, Linh Manh Ha, Samandram Sushilkumar Singh, Tetsuo Yamashita, Euki Yazaki, Endah Dwi Hartuti, Tetsuro Matsunaga, Tomoaki Ida, Tomoyoshi Nozaki, Takaaki Akaike, Tomoo Shiba, Jun-Ichi Kishikawa, Shinjiro Hamano, Kiyoshi Kita, Daniel Ken Inaoka

Adults of Schistosoma mansoni reside in the mesenteric veins, where they are naturally exposed to high levels of hydrogen sulfide (H2S). S. mansoni and other intestinal parasites have adapted to this sulfide-rich environment, but the evolved mechanisms to metabolize sulfide remain unelucidated. Here we reveal that the putative sulfide:quinone oxidoreductase (SQOR) encoded by S. mansoni is indeed an SQOR, catalyzing the first step of sulfide metabolism. We demonstrated that S. mansoni SQOR (SmSQOR) is expressed in eggs, cercaria and adult stages and localized in the mitochondria. The reaction catalyzed by SmSQOR was investigated using sulfane sulfur probe 4 (SSP4) and shown to require the co-presence of sulfide, quinone, and a sulfur acceptor, indicating a quaternary complex-mediated mechanism. Unlike human and bacterial SQORs, purified SmSQOR could not reduce quinones in the presence of sulfide alone unless sulfite, cyanide, or L-cysteine (but not coenzyme A or glutathione) was provided as the sulfur acceptor. In the presence of these sulfur acceptors, SmSQOR formed a long-lived charge-transfer (CT) complex, a transient electronically coupled association between electron donor and acceptor, as indicated by a broad band around 637-755 nm in the spectrum, which was associated with a partial loss of enzyme activity. Moreover, residues critical for CT complex formation and SQOR catalysis were identified. Using SSP4, we also demonstrated that SQOR was active in S. mansoni adult, egg, and cercaria stages. Taken together, these features suggest that metabolism of sulfide proceeds differently in S. mansoni than in humans.

成年曼氏血吸虫居住在肠系膜静脉中,在那里它们自然暴露于高水平的硫化氢(H2S)。mansoni和其他肠道寄生虫已经适应了这种富含硫化物的环境,但代谢硫化物的进化机制仍不清楚。本文揭示了mansoni编码的硫化物:醌氧化还原酶(SQOR)确实是一个SQOR,催化了硫化物代谢的第一步。我们证实了S. mansoni SQOR (SmSQOR)在卵、尾蚴和成虫阶段表达,并定位于线粒体。利用硫探针4 (SSP4)对SmSQOR催化的反应进行了研究,结果表明,该反应需要硫化物、醌和硫受体共存在,表明了一个季元络合物介导的机制。与人类和细菌sqor不同,纯化的SmSQOR不能在单独存在硫化物的情况下还原醌,除非提供亚硫酸盐、氰化物或l -半胱氨酸(但不包括辅酶A或谷胱甘肽)作为硫受体。在这些硫受体的存在下,SmSQOR形成了一个长寿命的电荷转移(CT)复合物,这是电子供体和受体之间的一种瞬态电子偶联,如光谱中约637-755 nm的宽带所示,这与酶活性的部分丧失有关。此外,还鉴定了对CT复合物形成和SQOR催化至关重要的残基。利用SSP4,我们还证明SQOR在曼氏血吸虫成虫、卵和尾蚴期都有活性。综上所述,这些特征表明,硫化物的代谢过程在曼氏血吸虫中与在人类中不同。
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引用次数: 0
The flavonoid GL-V9 induces oxidative stress mediated apoptosis in small cell lung cancer by promoting STEAP3 degradation. 类黄酮GL-V9通过促进STEAP3降解诱导氧化应激介导的小细胞肺癌细胞凋亡。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1016/j.freeradbiomed.2026.02.001
Jiawei Zhao, Xuefeng Zhang, Yanqing Zhou, Dongsheng Bai, Jiaying Du, Chen Zhou, Chunyang Gu, Yuxiang Wang, Yuan Gao, Na Lu, Yue Zhao

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by limited therapeutic options. In this study, we identified GL-V9 as a potent anti-SCLC agent that induces apoptosis through oxidative stress. GL-V9 significantly reduced SCLC cell viability in a dose-dependent manner and triggered apoptosis both in vitro and in xenograft models. Mechanistically, GL-V9 increased reactive oxygen species (ROS) levels and lipid peroxidation while impairing mitochondrial function, suggesting that its cytotoxic effects are mediated by oxidative stress. Drug-target interaction analyses revealed that GL-V9 directly binds to STEAP3, a key regulator of iron metabolism, and promotes its degradation via the ubiquitin-proteasome pathway. The loss of STEAP3 disrupted iron homeostasis and exacerbated oxidative stress. In contrast, STEAP3 overexpression attenuated ROS accumulation, mitochondrial damage, and apoptosis both in vitro and in vivo. Further investigation demonstrated that STEAP3 degradation decreased the stability of CISD2, a [2Fe-2S] cluster-containing mitochondrial protein essential for redox balance. GL-V9 downregulated CISD2 in a STEAP3-dependent manner, and restoring CISD2 expression significantly rescued cells from GL-V9-induced oxidative stress and apoptosis. Clinically, both STEAP3 and CISD2 are upregulated in SCLC tumors, and their elevated expression correlates with poor patient survival. Co-expression analysis associated these proteins with pathways involved in oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that GL-V9 induces apoptosis in SCLC by targeting STEAP3 for proteasomal degradation, thereby disrupting the STEAP3-CISD2 axis and promoting oxidative stress-driven cell death. This study identifies a previously unrecognized redox regulatory pathway in SCLC and proposes a potential therapeutic strategy centered on selective induction of oxidative stress.

小细胞肺癌(SCLC)是一种侵袭性恶性肿瘤,其特点是治疗选择有限。在这项研究中,我们发现GL-V9是一种有效的抗sclc药物,通过氧化应激诱导细胞凋亡。GL-V9以剂量依赖的方式显著降低SCLC细胞活力,并在体外和异种移植模型中引发细胞凋亡。在机制上,GL-V9增加活性氧(ROS)水平和脂质过氧化,同时损害线粒体功能,表明其细胞毒性作用是由氧化应激介导的。药物-靶标相互作用分析表明,GL-V9直接结合铁代谢的关键调节因子STEAP3,并通过泛素-蛋白酶体途径促进其降解。STEAP3的缺失破坏了铁稳态并加剧了氧化应激。相比之下,STEAP3过表达在体内和体外均可减轻ROS积累、线粒体损伤和细胞凋亡。进一步的研究表明,STEAP3的降解降低了CISD2的稳定性,CISD2是一种含有[2Fe-2S]簇的线粒体蛋白,对氧化还原平衡至关重要。GL-V9以steap3依赖的方式下调CISD2,恢复CISD2表达可显著拯救GL-V9诱导的细胞氧化应激和凋亡。在临床上,STEAP3和CISD2在SCLC肿瘤中均上调,其表达升高与患者生存不良相关。共表达分析将这些蛋白与氧化应激和线粒体功能障碍相关的途径联系起来。总之,这些发现表明GL-V9通过靶向STEAP3蛋白酶体降解诱导SCLC细胞凋亡,从而破坏STEAP3- cisd2轴并促进氧化应激驱动的细胞死亡。本研究确定了SCLC中一种以前未被认识的氧化还原调控途径,并提出了一种以选择性诱导氧化应激为中心的潜在治疗策略。
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引用次数: 0
Protective role of cichoriin and inulin against HFD-STZ-induced diabetic cardiomyopathy in mice via oxidative stress suppression and metabolic modulation. 菊甲苷和菊糖通过氧化应激抑制和代谢调节对hfd - stz诱导的小鼠糖尿病性心肌病的保护作用
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1016/j.freeradbiomed.2026.02.003
Nayan Kumar Sishu, Sajan George, Chinnadurai Immanuel Selvaraj

The distinctive characteristics of diabetic cardiomyopathy (DCM), a serious outcome of diabetes mellitus, are anomalies in the structure and functionality of the cardiac tissue. With a focus on their impact on inflammatory responses, oxidative injury, and the functioning of metabolic enzymes, this investigation aimed to evaluate the cardioprotective benefits of inulin and cichoriin over diabetes-related cardiomyopathy induced by high fat diet-streptozotocin (HFD-STZ) in mice. Diabetes was introduced in male Swiss albino mice by feeding them a high-fat diet followed by STZ injection and treated with cichoriin (50 and 100 mg/kg) or inulin (200 and 400 mg/kg). Serum biochemical, lipid, and cardiac injury markers were estimated. The metabolic enzyme activity (G6Pase, FBPase, ATPase, ENTPDase, 5'NT), oxidative stress markers (SOD, CAT, GSH, MDA, LDH), Angiotensin-Converting Enzyme (ACE) activity, and histological changes in the heart, pancreas, liver, and kidney, were assessed. NF-κB and Nrf2 immunohistochemistry was used to evaluate inflammatory and oxidative signalling. Treatment with inulin and cichoriin, especially at higher dosages, improved ACE activity, normalized metabolic enzyme activities, and substantially restored antioxidant enzyme levels. They reduced hyperglycemia, body weight loss, hyperlipidemia, and heart dysfunction with histological changes and fibrosis brought on by diabetes. Alongside these effects, cardiac tissues showed increased Nrf2 expression and decreased NF-κB, indicating the return of redox equilibrium and myocardial integrity. Thus, cichoriin and inulin substantially ameliorate the DCM by reducing oxidative injury, controlling glucose metabolism, and altering NF-κB/Nrf2 signaling pathways. These results demonstrate their potential for use as natural cardioprotective agents in the treatment of diabetic cardiomyopathy.

糖尿病性心肌病(DCM)是糖尿病的一种严重后果,其显著特征是心脏组织的结构和功能异常。通过对炎症反应、氧化损伤和代谢酶功能的影响,本研究旨在评估菊粉和菊石苷对小鼠高脂饮食链脲佐菌素(HFD-STZ)诱导的糖尿病相关心肌病的心脏保护作用。采用高脂饲料喂养雄性瑞士白化小鼠,然后注射STZ,再用菊甲苷(50和100 mg/kg)或菊粉(200和400 mg/kg)治疗。测定血清生化、血脂和心脏损伤指标。评估代谢酶活性(G6Pase、FBPase、ATPase、entpase、5’nt)、氧化应激标志物(SOD、CAT、GSH、MDA、LDH)、血管紧张素转换酶(ACE)活性以及心脏、胰腺、肝脏和肾脏的组织学变化。NF-κB和Nrf2免疫组化评价炎症和氧化信号。菊粉和菊苣苷处理,特别是高剂量处理,改善了ACE活性,使代谢酶活性正常化,并大大恢复了抗氧化酶水平。它们降低了高血糖、体重减轻、高脂血症和由糖尿病引起的组织学改变和纤维化的心功能障碍。除了这些作用外,心脏组织显示Nrf2表达增加,NF-κB减少,表明氧化还原平衡和心肌完整性的恢复。因此,纤毛虫素和菊糖通过减少氧化损伤、控制葡萄糖代谢和改变NF-κB/Nrf2信号通路,显著改善DCM。这些结果证明了它们在治疗糖尿病性心肌病中作为天然心脏保护剂的潜力。
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引用次数: 0
3-Deoxyanthocyanidins inhibit β-amyloid aggregation, toxicity, and mitochondrial dysfunction: Evidence from MC-65 cells and molecular dynamics simulations. 3-脱氧花青素抑制β-淀粉样蛋白聚集、毒性和线粒体功能障碍:来自MC-65细胞和分子动力学模拟的证据。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-01 DOI: 10.1016/j.freeradbiomed.2026.01.061
Rasheed A Abdulraheem, Ammar U Danazumi, Philipp Nitschke, Luke Gray Whiley, Abdulrahman Ibrahim Tudu, Ranil Coorey, Zhoyu Li, Prashant Bharadwaj, Vijay Jayasena, Stuart K Johnson, Ralph N Martins, W M A D Binosha Fernando

Accumulation of amyloid-beta (Aβ42) senile plaques in the brain is a hallmark of Alzheimer's disease (AD). Although some drug have been approvaled recently, none has demonstrated robust disease-modifying outcome. The 3-deoxyanthocyanidins (3-DXA) and their derivatives represent a more stable class of polyphenols, present at uniquely high concentrations in sorghum grains. Although 3-DXA exhibit strong potential to modulate protein aggregation processes, their effects on AD pathology remain unexplored. In this study, we investigated the inhibitory effects of three 3-DXA derivatives, apigeninidin chloride (AC), luteolinidin chloride (LC), and 7-methoxy apigeninidin (7-MAC), on Aβ42 aggregation and associated neurotoxicity. Thioflavin T fluorescence assay was employed to assess alterations in Aβ42 aggregation, while nuclear magnetic resonance spectroscopy and circular dichroism were used to evaluate compounds-protein interactions and secondary-structure changes. The neuroprotective effects of the three compounds were further examined in MC-65 cells under Aβ-induced toxicity. Additionally, generalized replica exchange with solute tempering based molecular dynamics simulations was conducted to explore the effects of AC and LC on Aβ42 dimer stability and β-sheet disruption. Our findings demonstrate that AC, LC, and 7-MAC significantly reduced Aβ42 aggregation by up to 88%, with AC and LC showing strong disruption of β-sheet structures. All three compounds significantly rescued MC-65 cells from Aβ42-induced toxicity (62-77%), accompanied by enhanced mitochondrial activity. Molecular dynamics simulations analyses further revealed that AC and LC disrupted hydrophobic interactions within Aβ42 dimers, contributing to destabilisation of neurotoxic aggregates. Overall, AC and LC exhibited strong multitarget activity against AD pathology by inhibiting Aβ42 aggregation, restoring intracellular energy balance, and disrupting key neurotoxic structural motifs.

淀粉样蛋白- β (a - β42)斑块的积累是阿尔茨海默病(AD)的一个标志,目前还没有治愈方法。3-脱氧花青素(3-DXA)及其衍生物是一类更稳定的多酚,在高粱籽粒中以独特的高浓度被发现。尽管3-DXA显示出调节蛋白质聚集过程的强大潜力,但它们对AD病理的影响在很大程度上仍未被探索。在本研究中,我们研究了3种3-DXA衍生物apigeninidin chloride (AC)、luteolinidin chloride (LC)和7-甲氧基apigeninidin (7-MAC)对a - β42聚集和相关神经毒性的抑制作用。采用硫黄素T (ThT)荧光法评估a - β42聚集的变化,采用圆二色性和核磁共振波谱法评估二级结构的变化。3-DXA衍生物在a β诱导的MC-65细胞中进一步检测了其神经保护作用。此外,采用基于溶质回火的广义复制交换分子动力学模拟研究了AC和LC对a - β42二聚体稳定性和β-薄片断裂的影响。我们的研究结果表明,AC、LC和7-MAC显著降低了a - β42的聚集,最高可达88%,其中AC和LC对β片结构的破坏尤为强烈。这三种化合物均能显著拯救MC-65细胞免受a β42诱导的毒性(62% -77%),并增强线粒体活性。分子动力学模拟分析显示,AC和LC破坏了Aβ42二聚体内的疏水相互作用,导致神经毒性聚集体的不稳定。总的来说,AC和LC通过抑制Aβ42聚集、恢复细胞内能量平衡和破坏关键的神经毒性结构基序,对AD病理表现出很强的多靶点活性。
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引用次数: 0
Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy. 番红花素通过激活pink1依赖性心肌细胞自噬来减轻阿霉素介导的心脏毒性。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-31 DOI: 10.1016/j.freeradbiomed.2026.01.040
Xin Su, Teng Fan, Zeyu Liu, Yuanyuan Huang, Jun Kan, Chuwen Liang, Yuwen Chen, Zhangqi Cao, Shuangli Zhu, Sijia Li, Kai Fu, Can Pan, Fang Wang, Bei Zhang, Liwu Fu

Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent cardiotoxicity. Currently, there are no effective strategies to prevent or reverse DOX-mediated myocardial injury, highlighting the urgent need for novel therapeutic approaches.

Objectives: In this study, the cardioprotective effects of crocin, a natural compound derived from Crocus sativus, were investigated in the context of DOX-mediated cardiotoxicity.

Methods: Cardiac function, mitochondrial morphology, ROS production, and ATP content were evaluated in both in vitro and in vivo models of DOX-mediated cardiotoxicity. RNA sequencing was performed to identify key regulatory pathways affected by crocin. Mitophagy-related mechanisms were investigated through molecular and cellular assays, including immunofluorescence and Western blot analysis of PTEN-induced kinase 1 (PINK1)-associated signaling. PINK1 knockdown and mitophagy inhibition were performed to assess the impact on the cardioprotective effects of crocin.

Results: Crocin treatment preserved cardiac function and mitigated DOX-mediated myocardial injury in both in vitro and in vivo models, as evidenced by restored left ventricular ejection fraction, reduced mitochondrial ROS accumulation, restoration of ATP production, and improved mitochondrial morphology. Transcriptomic analysis revealed that crocin upregulated PINK1 expression, a key initiator of mitophagy. Functional assays further confirmed that crocin restored mitophagy activity suppressed by DOX exposure. The cardioprotective effects of crocin were abolished upon PINK1 knockdown or mitophagy inhibitor, highlighting the essential role of PINK1-dependent mitophagy in mediating crocin's effects.

Conclusions: Crocin protects against doxorubicin-induced cardiotoxicity by activating PINK1-mediated mitophagy and maintaining mitochondrial homeostasis. These findings highlight crocin as a potential therapeutic agent for mitigating DOX-mediated cardiotoxicity.

多柔比星(DOX)是一种广泛使用的化疗药物,但其剂量依赖性心脏毒性限制了其临床应用。目前,还没有有效的策略来预防或逆转dox介导的心肌损伤,迫切需要新的治疗方法。目的:在本研究中,从藏红花中提取的天然化合物藏红花素在DOX介导的心脏毒性下的心脏保护作用进行了研究。方法:在体外和体内dox介导的心脏毒性模型中评估心功能、线粒体形态、ROS生成和ATP含量。进行RNA测序以确定藏红花素影响的关键调控途径。通过分子和细胞分析,包括pten诱导的激酶1 (PINK1)相关信号的免疫荧光和Western blot分析,研究了线粒体自噬的相关机制。通过下调PINK1和抑制线粒体自噬来评估藏红花素对心脏保护作用的影响。结果:在体外和体内模型中,藏红花素治疗均能保持心功能,减轻dox介导的心肌损伤,表现为左心室射血分数恢复,线粒体ROS积累减少,ATP生成恢复,线粒体形态改善。转录组学分析显示,藏红花素上调了PINK1的表达,PINK1是线粒体自噬的关键启动物。功能分析进一步证实藏红花素恢复了DOX暴露抑制的线粒体自噬活性。当PINK1被敲低或线粒体自噬抑制剂时,藏红花素的心脏保护作用被取消,这突出了PINK1依赖性线粒体自噬在介导藏红花素作用中的重要作用。结论:藏红花素通过激活pink1介导的线粒体自噬和维持线粒体稳态来保护阿霉素诱导的心脏毒性。这些发现突出了藏红花素作为减轻DOX介导的心脏毒性的潜在治疗剂。
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引用次数: 0
Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy. 醋酸改善糖脂代谢失调和神经炎症在糖尿病认知障碍通过增强线粒体自噬。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-30 DOI: 10.1016/j.freeradbiomed.2026.01.041
Jie Zheng, Yu An, Xin Zhang, Zhaoming Cao, Guangyi Xu, Jing Li, Jingya Wang, Li Chen, Yanhui Lu

Background: Diabetic cognitive impairment (DCI) is an increasingly recognized complication of type 2 diabetes mellitus (T2DM) with limited effective therapies. Short-chain fatty acids (SCFAs) have been implicated in metabolic regulation and neuronal health, yet comparisons of acetate, propionate, butyrate, and their mixture are limited, and the mechanisms underlying neuroprotection in DCI remain insufficiently clarified.

Methods: Ninety participants (healthy controls, T2DM, and DCI groups) were assessed for serum SCFA levels and cognitive performance using the Montreal Cognitive Assessment (MoCA). In parallel, a DCI mouse model established by a 24-week high-fat diet received 8-week supplementation with acetate, propionate, butyrate, or a mixture of the three. Glucolipid metabolism, spatial learning and memory, hippocampal neuronal damage, neuroinflammation, and mitophagy were evaluated. Based on consistency across the clinical and animal datasets, acetate was selected for mitophagy-focused mechanistic experiments, and pathway dependence was examined by co-administration of the autophagy inhibitor 3-methyladenine (3-MA).

Results: Clinically, serum acetate, propionate, and butyrate were lower in T2DM and DCI than in healthy controls; only acetate showed a further significant reduction in DCI compared with T2DM. All three SCFAs were positively associated with MoCA score and inversely associated with fasting blood glucose, whereas acetate additionally showed inverse associations with lipid parameters. In mice, SCFA supplementation alleviated metabolic dysfunction, spatial learning and memory, neuronal loss, and neuroinflammation, with acetate generally producing more consistent and numerically greater improvements across these endpoints. Mechanistically, acetate enhanced hippocampal mitophagy by restoring LC3-TOMM20 colocalization and activating the PINK1/Parkin pathway. Importantly, 3-MA partially attenuated these benefits, indicating a mitophagy-dependent mechanism.

Conclusions: These integrated clinical and experimental data support a "SCFAs-mitophagy-neuroinflammation" axis linking systemic metabolism to neuronal vulnerability in DCI, and identify acetate as a promising SCFA that may enhance neuronal resilience through mitophagy activation.

背景:糖尿病性认知障碍(DCI)是2型糖尿病(T2DM)的一种日益被认可的并发症,有效治疗方法有限。短链脂肪酸(SCFAs)与代谢调节和神经元健康有关,但醋酸酯、丙酸酯、丁酸酯及其混合物的比较有限,DCI中神经保护的机制仍不充分明确。方法:使用蒙特利尔认知评估(MoCA)评估90名参与者(健康对照组、T2DM组和DCI组)的血清SCFA水平和认知表现。同时,通过24周高脂饮食建立的DCI小鼠模型在8周内补充乙酸、丙酸、丁酸或三者的混合物。评估糖脂代谢、空间学习和记忆、海马神经元损伤、神经炎症和线粒体自噬。基于临床和动物数据集的一致性,选择醋酸酯进行以线粒体自噬为重点的机制实验,并通过联合给药自噬抑制剂3-甲基腺嘌呤(3-MA)来检测途径依赖性。结果:T2DM和DCI患者血清乙酸、丙酸、丁酸均低于健康对照组;与T2DM相比,只有醋酸盐能进一步显著降低DCI。这三种scfa均与MoCA评分呈正相关,与空腹血糖呈负相关,而乙酸与脂质参数呈负相关。在小鼠中,补充SCFA减轻了代谢功能障碍、空间学习和记忆、神经元丧失和神经炎症,醋酸盐通常在这些终点上产生更一致和更大的改善。从机制上讲,醋酸盐通过恢复LC3-TOMM20共定位和激活PINK1/Parkin通路来增强海马有丝分裂。重要的是,3-MA部分减弱了这些益处,表明有丝分裂依赖机制。结论:这些综合的临床和实验数据支持“SCFA -线粒体自噬-神经炎症”轴将DCI的全身代谢与神经元易损性联系起来,并确定醋酸盐是一种有希望的SCFA,可能通过线粒体自噬激活来增强神经元的恢复能力。
{"title":"Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy.","authors":"Jie Zheng, Yu An, Xin Zhang, Zhaoming Cao, Guangyi Xu, Jing Li, Jingya Wang, Li Chen, Yanhui Lu","doi":"10.1016/j.freeradbiomed.2026.01.041","DOIUrl":"10.1016/j.freeradbiomed.2026.01.041","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cognitive impairment (DCI) is an increasingly recognized complication of type 2 diabetes mellitus (T2DM) with limited effective therapies. Short-chain fatty acids (SCFAs) have been implicated in metabolic regulation and neuronal health, yet comparisons of acetate, propionate, butyrate, and their mixture are limited, and the mechanisms underlying neuroprotection in DCI remain insufficiently clarified.</p><p><strong>Methods: </strong>Ninety participants (healthy controls, T2DM, and DCI groups) were assessed for serum SCFA levels and cognitive performance using the Montreal Cognitive Assessment (MoCA). In parallel, a DCI mouse model established by a 24-week high-fat diet received 8-week supplementation with acetate, propionate, butyrate, or a mixture of the three. Glucolipid metabolism, spatial learning and memory, hippocampal neuronal damage, neuroinflammation, and mitophagy were evaluated. Based on consistency across the clinical and animal datasets, acetate was selected for mitophagy-focused mechanistic experiments, and pathway dependence was examined by co-administration of the autophagy inhibitor 3-methyladenine (3-MA).</p><p><strong>Results: </strong>Clinically, serum acetate, propionate, and butyrate were lower in T2DM and DCI than in healthy controls; only acetate showed a further significant reduction in DCI compared with T2DM. All three SCFAs were positively associated with MoCA score and inversely associated with fasting blood glucose, whereas acetate additionally showed inverse associations with lipid parameters. In mice, SCFA supplementation alleviated metabolic dysfunction, spatial learning and memory, neuronal loss, and neuroinflammation, with acetate generally producing more consistent and numerically greater improvements across these endpoints. Mechanistically, acetate enhanced hippocampal mitophagy by restoring LC3-TOMM20 colocalization and activating the PINK1/Parkin pathway. Importantly, 3-MA partially attenuated these benefits, indicating a mitophagy-dependent mechanism.</p><p><strong>Conclusions: </strong>These integrated clinical and experimental data support a \"SCFAs-mitophagy-neuroinflammation\" axis linking systemic metabolism to neuronal vulnerability in DCI, and identify acetate as a promising SCFA that may enhance neuronal resilience through mitophagy activation.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"580-597"},"PeriodicalIF":8.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition. 靶向结核分枝杆菌GAPDH通过失调酶活性、氧化还原动力学和铁获取引起有效的杀菌反应。
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-30 DOI: 10.1016/j.freeradbiomed.2026.01.044
Zahid Gani, Mohammad Naiyaz Ahmad, Anurag Sindhu, Ajay Kumar, Anjali Kumari, Mohmmad Imran, Pradip Malik, Asmita Dhiman, Vinay Kumar Yadav, Gaddam Laxmi Priya, Gattadi Sravani, Nisheeth Agarwal, Rajender Kumar, Prabha Garg, Arunava Dasgupta, Sidharth Chopra, Manoj Raje, Chaaya Iyengar Raje

Mycobacterium tuberculosis (Mtb) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is indispensable for glycolysis, it also performs several critical non-metabolic functions. In the present study, we demonstrate that CRISPRi silencing of GAPDH inhibited enzyme activity and iron acquisition via human transferrin (Tf)/lactoferrin (Lf). GAPDH silencing also enhanced reactive oxygen species (ROS) and ROS induced damage suggesting its role as a redox sensor. We then examined the impact of GAPDH inhibition in Mtb using small molecule inhibitors. Vitamin C (VC) was selected considering its potent bactericidal effects against Mtb and its inhibition of human GAPDH resulting in its efficacy against cancer cells. The GAPDH inhibitors Ethyl bromopyruvate (EBP) and Koningic acid (KA) are anti-cancer agents that target the glycolytic activity of GAPDH. In contrast, TCH346 was identified as a neuroprotective agent, wherein it targets the non-metabolic function of GAPDH induced apoptotic signalling. The effects of inhibitors, alone or in combination with VC mirrored the cellular effects of GAPDH silencing, resulting in significant anti-bacterial activity. VC induced iron mobilization which coupled with GAPDH inhibitors induced a veritable "double whammy" resulting in massive increase in ROS and downstream effects. The efficacy of these treatments was assessed in a murine model, confirming that VC augmented the potent anti-tubercular activity induced by EBP and TCH346. Overall, this study identifies the crucial function of Mtb GAPDH as a redox sensor and highlights the potential of targeting its pleiotropic cellular functions towards drug discovery. In addition, the efficacy of TCH346 provides an opportunity of drug-repurposing as a strategy for therapy.

结核分枝杆菌(Mtb)甘油醛-3-磷酸脱氢酶(GAPDH)在糖酵解过程中是必不可少的,它还具有几个关键的非代谢功能。在本研究中,我们证明CRISPRi沉默GAPDH抑制酶活性和通过人转铁蛋白(Tf)/乳铁蛋白(Lf)获得铁。GAPDH沉默还能增强活性氧(ROS)和ROS诱导的损伤,提示其作为氧化还原传感器的作用。然后,我们使用小分子抑制剂检查了GAPDH抑制对结核分枝杆菌的影响。选择维生素C (VC)考虑到其对结核分枝杆菌的有效杀菌作用和对人GAPDH的抑制作用,从而对癌细胞具有抑制作用。GAPDH抑制剂溴丙酮酸乙酯(EBP)和Koningic acid (KA)是靶向GAPDH糖酵解活性的抗癌药物。相反,TCH346被鉴定为一种神经保护剂,其靶向GAPDH诱导的凋亡信号传导的非代谢功能。抑制剂单独使用或与VC联合使用的效果反映了GAPDH沉默的细胞效应,从而产生显著的抗菌活性。VC诱导的铁动员与GAPDH抑制剂联合引起了名副其实的“双重打击”,导致ROS和下游效应大量增加。在小鼠模型中对这些治疗的疗效进行了评估,证实VC增强了EBP和TCH346诱导的有效抗结核活性。总的来说,本研究确定了Mtb GAPDH作为氧化还原传感器的关键功能,并强调了针对其多功能性细胞功能进行药物发现的潜力。此外,TCH346的疗效为药物再利用作为治疗策略提供了机会。
{"title":"Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition.","authors":"Zahid Gani, Mohammad Naiyaz Ahmad, Anurag Sindhu, Ajay Kumar, Anjali Kumari, Mohmmad Imran, Pradip Malik, Asmita Dhiman, Vinay Kumar Yadav, Gaddam Laxmi Priya, Gattadi Sravani, Nisheeth Agarwal, Rajender Kumar, Prabha Garg, Arunava Dasgupta, Sidharth Chopra, Manoj Raje, Chaaya Iyengar Raje","doi":"10.1016/j.freeradbiomed.2026.01.044","DOIUrl":"10.1016/j.freeradbiomed.2026.01.044","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is indispensable for glycolysis, it also performs several critical non-metabolic functions. In the present study, we demonstrate that CRISPRi silencing of GAPDH inhibited enzyme activity and iron acquisition via human transferrin (Tf)/lactoferrin (Lf). GAPDH silencing also enhanced reactive oxygen species (ROS) and ROS induced damage suggesting its role as a redox sensor. We then examined the impact of GAPDH inhibition in Mtb using small molecule inhibitors. Vitamin C (VC) was selected considering its potent bactericidal effects against Mtb and its inhibition of human GAPDH resulting in its efficacy against cancer cells. The GAPDH inhibitors Ethyl bromopyruvate (EBP) and Koningic acid (KA) are anti-cancer agents that target the glycolytic activity of GAPDH. In contrast, TCH346 was identified as a neuroprotective agent, wherein it targets the non-metabolic function of GAPDH induced apoptotic signalling. The effects of inhibitors, alone or in combination with VC mirrored the cellular effects of GAPDH silencing, resulting in significant anti-bacterial activity. VC induced iron mobilization which coupled with GAPDH inhibitors induced a veritable \"double whammy\" resulting in massive increase in ROS and downstream effects. The efficacy of these treatments was assessed in a murine model, confirming that VC augmented the potent anti-tubercular activity induced by EBP and TCH346. Overall, this study identifies the crucial function of Mtb GAPDH as a redox sensor and highlights the potential of targeting its pleiotropic cellular functions towards drug discovery. In addition, the efficacy of TCH346 provides an opportunity of drug-repurposing as a strategy for therapy.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"54-70"},"PeriodicalIF":8.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
BMAL1 downregulation exacerbates age-related nonalcoholic steatohepatitis by promoting NLRP3 inflammasome activation via HIF-1ɑ-mediated glycolysis. BMAL1下调通过HIF-1介导的糖酵解促进NLRP3炎性体激活,加重年龄相关性非酒精性脂肪性肝炎
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-30 DOI: 10.1016/j.freeradbiomed.2026.01.058
Yujie Ren, Dongying Lv, Jiayan Chen, Wenjing Chen, Chu Chen, Lizong Zhang, Jue Tu, Keyan Zhu, Dejun Wang, Zhaowei Cai

Introduction: Epidemiological studies have demonstrated higher incidence and mortality rate of nonalcoholic steatohepatitis (NASH) in the elderly population than in younger groups. However, the mechanisms underlying this age-related exacerbation remain poorly understood.

Objective: This study aimed to elucidate the specific pathways through which aging exacerbates NASH progression, using an integrated in vivo and in vitro model.

Methods: Aged (18-month-old) and young (6-week-old) mice were fed a high-fat diet (HFD) for 16 weeks to induce NASH. A senescence-associated cellular model of NASH was established by co-treating murine hepatocyte AML-12 with H2O2 and free fatty acid (FFA). Gene expression profiling of liver tissue was performed using RNA sequencing to identify molecular signatures. Interventions were as follows: (1) In vitro, BMAL1 overexpression plasmids were transfected into AML-12 cells, followed by treatment with 2-deoxy-D-glucose (2-DG, a glycolysis inhibitor) and 2-methoxyestradiol (2-ME2, a HIF-1α inhibitor); (2) in vivo, hepatocyte-specific BMAL1 overexpression was achieved in aged HFD-fed mice through adeno-associated virus serotype 8 (AAV8) delivery. Mechanism validation was performed using biochemical assays, Western blot, cell staining, molecular docking, and Co-IP.

Results: Aged HFD-fed mice exhibited more severe NASH phenotypes than young mice. Transcriptomic analysis identified NLRP3-related signaling and circadian rhythm pathways as central contributors to age-specific NASH pathogenesis. These mice also exhibited elevated NLRP3 inflammasome activity, enhanced glycolysis, and reduced BMAL1 expression. In senescent NASH cells, BMAL1 overexpression along with 2-DG or 2-ME2 treatment significantly downregulated NLRP3 expression and attenuated lipid accumulation, inflammation, oxidative stress, and fibrosis. Mechanistically, BMAL1 directly bound to HIF-1α, thereby suppressing glycolysis. Hepatocyte-specific BMAL1 overexpression in aged HFD-fed mice markedly inhibited glycolysis and NLRP3 activation, resulting in an improvement in NASH-related pathologies.

Conclusion: This study revealed a novel mechanism in which BMAL1 downregulation under aging and HFD conditions promotes NASH progression by binding to HIF-1α and modulating the glycolysis-NLRP3 inflammasome axis.

流行病学研究表明,老年人非酒精性脂肪性肝炎(NASH)的发病率和死亡率高于年轻人。然而,这种与年龄相关的恶化的机制仍然知之甚少。目的:本研究旨在通过体内和体外综合模型阐明衰老加剧NASH进展的具体途径。方法:老龄小鼠(18月龄)和幼龄小鼠(6周龄)喂食高脂饮食(HFD) 16周,诱导NASH。用H2O2和游离脂肪酸(FFA)共处理小鼠肝细胞AML-12,建立衰老相关的NASH细胞模型。肝组织基因表达谱使用RNA测序来识别分子特征。干预措施如下:(1)体外将BMAL1过表达质粒转染至AML-12细胞,然后用2-脱氧-d -葡萄糖(2-DG,糖酵解抑制剂)和2-甲氧基雌二醇(2-ME2, HIF-1α抑制剂)处理;(2)在体内,通过腺相关病毒血清型8 (AAV8)递送,在老年hmd喂养小鼠中实现了肝细胞特异性BMAL1的过表达。通过生化分析、Western blot、细胞染色、分子对接和Co-IP进行机制验证。结果:老年hfd喂养小鼠比年轻小鼠表现出更严重的NASH表型。转录组学分析确定nlrp3相关信号通路和昼夜节律通路是年龄特异性NASH发病机制的主要因素。这些小鼠还表现出NLRP3炎性体活性升高,糖酵解增强,BMAL1表达降低。在衰老NASH细胞中,BMAL1过表达以及2-DG或2-ME2处理显著下调NLRP3表达,减轻脂质积累、炎症、氧化应激和纤维化。在机制上,BMAL1直接与HIF-1α结合,从而抑制糖酵解。老年hfd喂养小鼠肝细胞特异性BMAL1过表达显著抑制糖酵解和NLRP3激活,导致nash相关病理改善。结论:本研究揭示了衰老和HFD条件下BMAL1下调通过与HIF-1α结合并调节糖酵解- nlrp3炎症小体轴促进NASH进展的新机制。
{"title":"BMAL1 downregulation exacerbates age-related nonalcoholic steatohepatitis by promoting NLRP3 inflammasome activation via HIF-1ɑ-mediated glycolysis.","authors":"Yujie Ren, Dongying Lv, Jiayan Chen, Wenjing Chen, Chu Chen, Lizong Zhang, Jue Tu, Keyan Zhu, Dejun Wang, Zhaowei Cai","doi":"10.1016/j.freeradbiomed.2026.01.058","DOIUrl":"10.1016/j.freeradbiomed.2026.01.058","url":null,"abstract":"<p><strong>Introduction: </strong>Epidemiological studies have demonstrated higher incidence and mortality rate of nonalcoholic steatohepatitis (NASH) in the elderly population than in younger groups. However, the mechanisms underlying this age-related exacerbation remain poorly understood.</p><p><strong>Objective: </strong>This study aimed to elucidate the specific pathways through which aging exacerbates NASH progression, using an integrated in vivo and in vitro model.</p><p><strong>Methods: </strong>Aged (18-month-old) and young (6-week-old) mice were fed a high-fat diet (HFD) for 16 weeks to induce NASH. A senescence-associated cellular model of NASH was established by co-treating murine hepatocyte AML-12 with H<sub>2</sub>O<sub>2</sub> and free fatty acid (FFA). Gene expression profiling of liver tissue was performed using RNA sequencing to identify molecular signatures. Interventions were as follows: (1) In vitro, BMAL1 overexpression plasmids were transfected into AML-12 cells, followed by treatment with 2-deoxy-D-glucose (2-DG, a glycolysis inhibitor) and 2-methoxyestradiol (2-ME2, a HIF-1α inhibitor); (2) in vivo, hepatocyte-specific BMAL1 overexpression was achieved in aged HFD-fed mice through adeno-associated virus serotype 8 (AAV8) delivery. Mechanism validation was performed using biochemical assays, Western blot, cell staining, molecular docking, and Co-IP.</p><p><strong>Results: </strong>Aged HFD-fed mice exhibited more severe NASH phenotypes than young mice. Transcriptomic analysis identified NLRP3-related signaling and circadian rhythm pathways as central contributors to age-specific NASH pathogenesis. These mice also exhibited elevated NLRP3 inflammasome activity, enhanced glycolysis, and reduced BMAL1 expression. In senescent NASH cells, BMAL1 overexpression along with 2-DG or 2-ME2 treatment significantly downregulated NLRP3 expression and attenuated lipid accumulation, inflammation, oxidative stress, and fibrosis. Mechanistically, BMAL1 directly bound to HIF-1α, thereby suppressing glycolysis. Hepatocyte-specific BMAL1 overexpression in aged HFD-fed mice markedly inhibited glycolysis and NLRP3 activation, resulting in an improvement in NASH-related pathologies.</p><p><strong>Conclusion: </strong>This study revealed a novel mechanism in which BMAL1 downregulation under aging and HFD conditions promotes NASH progression by binding to HIF-1α and modulating the glycolysis-NLRP3 inflammasome axis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"562-579"},"PeriodicalIF":8.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease. 多巴胺能神经元rab27依赖性线粒体挤压驱动帕金森病MPTP小鼠模型的神经炎症和神经退行性变
IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-29 DOI: 10.1016/j.freeradbiomed.2026.01.053
Yingqi Xu, Junyu Li, Shanshan Ma, Ting Yang, Ziyue Shen, Mingtao Li, Qiaoying Huang

Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional Rab27 knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.

受损线粒体的挤压正在成为先天免疫激活的触发因素。以严重线粒体功能障碍为特征的帕金森病(PD)可能涉及类似的机制。在这里,我们报道了在1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)小鼠PD模型中,多巴胺能神经元将受损的线粒体释放到细胞外空间。这些神经元来源的线粒体随后被神经胶质细胞吞噬,引发强烈的炎症反应。自噬抑制不影响线粒体释放,表明非典型挤压途径。线粒体损伤后,Rab27a和Rab27b转运至线粒体外膜,介导线粒体从多巴胺能神经元输出。多巴胺能神经元条件性Rab27敲低可减少细胞外线粒体积累、小胶质细胞激活、抗病毒信号和多巴胺能神经变性。总之,这些发现表明rab27依赖性线粒体挤压是PD患者多巴胺能神经元损伤与神经炎症和神经退行性变耦合的关键机制。
{"title":"Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease.","authors":"Yingqi Xu, Junyu Li, Shanshan Ma, Ting Yang, Ziyue Shen, Mingtao Li, Qiaoying Huang","doi":"10.1016/j.freeradbiomed.2026.01.053","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.01.053","url":null,"abstract":"<p><p>Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional Rab27 knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Free Radical Biology and Medicine
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