Pei Yandong, Ren Dongfeng, Yin Yuanhao, Shi Jiajia, Ai Qianyuan, Hao Wenxin, Luo Xiaofan, Zhang Chenyue, Zhao Yanping, Bai Chenyu, Zhu Lin, Wang Qiong, Li Shuangling, Zhang Yuwei, Lu Jiangtao, Liu Lin, Zhou Lin, Wu Yuli, Weng Yiqi, Jing Yongle, Lu Chengzhi, Cui Yujie, Zheng Hao, Li Yanjun, Chen Guo, Hu Gang, Chen Quan, Liao Xudong
State Key Laboratory of Medicinal Chemistry Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences (Y.P., D.R., Y.Y., J.S., Q.A., W.H., X. Luo, C.B., L. Zhu, Q.W., S.L., Y. Zhang, J.L., L.L., H.Z., Y.L., G.C., Q.C., X. Liao), Nankai University, China.
School of Statistics and Data Science, LPMC and KLMDASR (C.Z., Y. Zhao, G.H.), Nankai University, China.
Circ Res. 2025 Jan 17;136(2):e1-e19. doi: 10.1161/CIRCRESAHA.124.325156. Epub 2024 Dec 10.
Pulmonary hypertension (PH) is associated with endothelial dysfunction. However, the cause of endothelial dysfunction and its impact on PH remain incompletely understood. We aimed to investigate whether the hypoxia-inducible FUNDC1 (FUN14 domain-containing 1)-dependent mitophagy pathway underlies PH pathogenesis and progression.
We first analyzed FUNDC1 protein levels in lung samples from patients with PH and animal models. Using rodent PH models induced by HySu (hypoxia+SU5416) or chronic hypoxia, we further investigated PH pathogenesis and development in response to global and cell-type-specific loss/gain-of-function. We also investigated the spontaneous PH in mice with inducible loss of endothelial . In addition, histological, metabolic, and transcriptomic studies were performed to delineate molecular mechanisms. Finally, findings were validated in vivo by compound deficiency of HIF2α (hypoxia-inducible factor 2α; ) and pharmacological intervention.
FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global deficiency exacerbated PH, while its overexpression was protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial protected against PH before and after the onset of disease. Mechanistically, deficiency impaired basal mitophagy in endothelial cells, leading to the accumulation of dysfunctional mitochondria, metabolic reprogramming toward aerobic glycolysis, pseudohypoxia, and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, -deficient endothelial cells increased IGFBP2 (insulin-like growth factor-binding protein 2) secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence, or IGFBP2.
Collectively, we show that FUNDC1-mediated basal mitophagy is critical for endothelial homeostasis, and its disruption instigates PH pathogenesis. Given that similar changes in FUNDC1 and IGFBP2 were observed in PH patients, our findings are of significant clinical relevance and provide novel therapeutic strategies for PH.
肺动脉高压（PH）与内皮功能障碍有关。然而，内皮功能障碍的原因及其对PH的影响仍未完全明确。我们旨在研究缺氧诱导的依赖FUNDC1（含FUN14结构域蛋白1）的线粒体自噬途径是否是PH发病机制及病情进展的基础。
我们首先分析了PH患者和动物模型肺组织样本中FUNDC1蛋白水平。使用由HySu（缺氧+SU5416）或慢性缺氧诱导的啮齿动物PH模型，我们进一步研究了在整体和细胞类型特异性功能丧失/功能获得情况下PH的发病机制和发展过程。我们还研究了内皮细胞诱导性缺失的小鼠的自发性PH。此外，进行了组织学、代谢和转录组学研究以阐明分子机制。最后，通过HIF2α（缺氧诱导因子2α）复合缺陷和药物干预在体内验证了研究结果。
临床受试者和动物模型的PH肺血管中FUNDC1蛋白水平降低。整体缺陷会加重PH，而其过表达则具有保护作用。FUNDC1的作用是由内皮细胞而非平滑肌细胞介导的。此外，出生后小鼠内皮细胞的诱导性缺失足以自发导致PH，而增强内皮细胞功能可在疾病发生前后预防PH。从机制上讲，缺陷会损害内皮细胞的基础线粒体自噬，导致功能失调的线粒体积累，代谢重编程向有氧糖酵解、假性缺氧和衰老发展，可能是通过mtROS-HIF2α信号通路。随后，缺陷的内皮细胞增加了IGFBP2（胰岛素样生长因子结合蛋白2）的分泌，从而驱动肺动脉重塑以引发PH。最后，体内原理验证研究表明，通过靶向内皮线粒体自噬、假性缺氧、衰老或IGFBP2对改善PH具有显著疗效。
总体而言，我们表明FUNDC1介导的基础线粒体自噬对于内皮细胞稳态至关重要，其破坏会引发PH发病机制。鉴于在PH患者中观察到FUNDC1和IGFBP2有类似变化，我们的研究结果具有重要的临床意义，并为PH提供了新的治疗策略。
