Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension.

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-09-25 DOI:10.1084/jem.20231568
Maki Niihori, Joel James, Mathews V Varghese, Nolan McClain, Odunayo Susan Lawal, Rohit C Philip, Brenda K Baggett, Dmitry A Goncharov, Vinicio de Jesus Perez, Elena A Goncharova, Ruslan Rafikov, Olga Rafikova
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引用次数: 0

Abstract

Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.

线粒体是肺动脉高压血管生成模式的主要决定因素。
肺血管生成受损在肺动脉高压(PAH)的进展和患者死亡率中起着关键作用,但驱动这一过程的分子机制仍然是个谜。我们的研究发现了线粒体功能障碍(MD)(由 NFU1 基因的人源化突变引起)与成人肺血管生成严重受损之间的惊人联系。在 NFU1G206C 模型中,恢复 NFU1 下游靶标硫辛酸(LA)的生物利用度可缓解 MD 和血管生成不足,并挽救进行性 PAH 表型。值得注意的是,在特发性 PAH(iPAH)患者的肺部也发现了明显的 NFU1 表达和信号传导不足,这强调了这项研究的意义并不局限于 NFU1 基因突变病例。PAH 患者来源的肺动脉内皮细胞(PAECs)在补充 LA 后线粒体功能得到了明显改善,从而将 LA 作为一种潜在的治疗方法。总之,本研究揭示了 MD 在肺血管生成失调和 PAH 表现中的新作用,强调了在未发现 NFU1/LA 缺乏的 PAH 患者中纠正 MD 的必要性。
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
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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