Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-10-28 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.102424
Xing Chang, Hao Zhou, Jinlin Hu, Teng Ge, Kunyang He, Ye Chen, Rongjun Zou, Xiaoping Fan
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引用次数: 0

Abstract

Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries and involves various complex pathological mechanisms and factors. Previous studies have demonstrated a close association between atherosclerosis and inflammatory damage, metabolic disorders, and gut microbiota. It is also closely linked to several cellular processes, such as endothelial cell pyroptosis, ferroptosis, mitophagy, mitochondrial dynamics, and mitochondrial biogenesis. Mitophagy has been recognized as a previously unexplored mechanism contributing to endothelial injury in atherosclerosis. Our study aims to further elucidate the potential relationship and mechanisms between AS-induced mitophagy dysfunction and the interaction of TMBIM6 and NDUFS4. Data from the study demonstrated that atherosclerosis in AS mice was associated with substantial activation of inflammatory and oxidative stress damage, along with a marked reduction in endothelial mitophagy expression and increased pathological mitochondrial fission, leading to mitochondrial homeostasis disruption. However, under pharmacological intervention, mitophagy levels significantly increased, pathological mitochondrial fission was notably reduced, and oxidative stress and inflammatory damage were suppressed, while necroptotic pathways in endothelial cells were significantly blocked. Interestingly, the deletion of TMBIM6 or NDUFS4 in animal models or cell lines markedly impaired the therapeutic effects of the drug, disrupting its regulation of mitophagy and mitochondrial fission, and leading to the re-emergence of inflammatory responses and oxidative stress damage. Metabolomics analysis further revealed that autophagy plays a pivotal regulatory role during drug intervention and after genetic modification of TMBIM6 and NDUFS4. The activation of autophagy (macroautophagy/mitophagy) alleviated the negative effects of mitochondrial fission and inflammatory damage induced by lipid stress in endothelial cells, a regulatory mechanism likely associated with the TMBIM6-NDUFS4 axis. Subsequent animal gene modification experiments demonstrated that knocking out TMBIM6-NDUFS4 negates the therapeutic effects of the drug on lipid-induced damage and metabolic function. In summary, our research reveals a phenotypic regulatory mechanism of endothelial cell stress damage through mitophagy, influenced by the interaction of TMBIM6 and NDUFS4. Pharmacological intervention can restore mitochondrial homeostasis in endothelial cells by regulating mitophagy via the TMBIM6-NDUFS4 pathway. This novel insight suggests that TMBIM6-NDUFS4 may serve as a key therapeutic target for atherosclerosis.

通过脂质-硒结合药物靶向线粒体会导致苹果酸/富马酸耗竭,并诱导有丝分裂介导的坏死抑制。
动脉粥样硬化(AS)是一种主要影响大、中动脉的慢性血管疾病,涉及各种复杂的病理机制和因素。以往的研究表明,动脉粥样硬化与炎症损伤、代谢紊乱和肠道微生物群密切相关。动脉粥样硬化还与多个细胞过程密切相关,如内皮细胞热噬、铁噬、有丝分裂、线粒体动力学和线粒体生物生成。有丝分裂被认为是动脉粥样硬化中导致内皮损伤的一种尚未探索的机制。我们的研究旨在进一步阐明AS诱导的有丝分裂功能障碍与TMBIM6和NDUFS4相互作用之间的潜在关系和机制。研究数据表明,AS小鼠的动脉粥样硬化与炎症和氧化应激损伤的大量激活有关,同时内皮细胞有丝分裂表达明显减少,病理性线粒体裂变增加,导致线粒体平衡紊乱。然而,在药物干预下,内皮细胞的有丝分裂水平明显提高,病理性线粒体裂变明显减少,氧化应激和炎症损伤得到抑制,同时内皮细胞的坏死通路被明显阻断。有趣的是,在动物模型或细胞系中删除 TMBIM6 或 NDUFS4 会明显削弱药物的治疗效果,破坏其对有丝分裂和线粒体分裂的调控,导致炎症反应和氧化应激损伤的再次出现。代谢组学分析进一步揭示了自噬在药物干预期间以及 TMBIM6 和 NDUFS4 基因修饰后起着关键的调控作用。自噬(大自噬/小自噬)的激活减轻了内皮细胞线粒体裂变和脂质应激诱导的炎症损伤的负面影响,这种调控机制可能与 TMBIM6-NDUFS4 轴有关。随后的动物基因修饰实验表明,敲除 TMBIM6-NDUFS4 会抵消药物对脂质诱导的损伤和代谢功能的治疗效果。总之,我们的研究揭示了通过有丝分裂对内皮细胞应激损伤的表型调控机制,该机制受 TMBIM6 和 NDUFS4 相互作用的影响。药理干预可通过 TMBIM6-NDUFS4 途径调节有丝分裂,从而恢复内皮细胞的线粒体稳态。这一新颖见解表明,TMBIM6-NDUFS4 可作为动脉粥样硬化的关键治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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