BACKGROUND 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. METHODS 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 Fundc1 loss/gain-of-function. We also investigated the spontaneous PH in mice with inducible loss of endothelial Fundc1. 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; Epas1) and pharmacological intervention. RESULTS FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global Fundc1 deficiency exacerbated PH, while its overexpression is protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial Fundc1 in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial Fundc1 protected against PH before and after the onset of disease. Mechanistically, Fundc1 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, Fundc1-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. CONCLUSIONS 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.

中文翻译：

---

内皮 FUNDC1 缺陷导致肺动脉高压。


背景 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 的影响仍不完全清楚。我们旨在研究缺氧诱导的 FUNDC1 （FUN14 结构域包含 1） 依赖性线粒体自噬途径是否是 PH 发病机制和进展的基础。方法 我们首先分析了 PH 患者和动物模型肺样本中 FUNDC1 蛋白水平。使用 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 PH 响应整体和细胞类型特异性 Fundc1 丧失/获得功能的发病机制和发展。我们还研究了内皮 Fundc1 诱导性缺失的小鼠的自发性 PH。此外，还进行了组织学、代谢和转录组学研究以描述分子机制。最后，通过 HIF2α （缺氧诱导因子 2α;EPAS1） 和药物干预。结果 临床受试者和动物模型 PH 肺血管中 FUNDC1 蛋白水平降低。Global Fundc1 缺陷加剧了 PH，而其过表达具有保护作用。FUNDC1 的作用是由内皮细胞而不是平滑肌细胞介导的。此外，出生后小鼠内皮 Fundc1 的诱导性丢失足以自发引起 PH，而增加内皮 Fundc1 在疾病发作前后可防止 PH。从机制上讲，Fundc1 缺陷损害了内皮细胞中的基底线粒体自噬，导致功能失调的线粒体积累、向有氧糖酵解的代谢重编程、假性缺氧和衰老，这可能是通过 mtROS-HIF2α 信号通路。 随后，Fundc1 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刺激 PH。最后，原理验证体内研究表明，通过靶向内皮线粒体自噬、假性缺氧、衰老或 IGFBP2 对 PH 改善具有显着疗效。结论 总的来说，我们表明 FUNDC1 介导的基础线粒体自噬对内皮稳态至关重要，其破坏会引发 PH 发病机制。鉴于在 PH 患者中观察到 FUNDC1 和 IGFBP2 的类似变化，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。