Targeting ATP11B KLF4 YAP Axis Repairs Mitochondrial function and Inhibits Neuronal Ferroptosis to Attenuate Age Related Cognitive Decline

Brain aging is accompanied by cognitive decline and an increased risk of neurodegenerative diseases, with neuronal aging being a key link between healthy aging and disease. Studies have shown that the earliest damage to the integrity of the blood-brain barrier occurs in the hippocampus, leading abnormal accumulation of Fe. However, the mechanism through which this drives neuronal aging remains unclear. Via single cell and spatial transcriptomic analyses, this study focused on the phospholipid flippase ATP11B. We found that ATP11B deficiency facilitates the transport of Fe from ependymal cells to hippocampal neurons, activates the Hippo signaling pathway, and induces mitochondrial respiratory dysfution and dynamic imbalance, leading to neuronal ferroptosis and exacerbating aging phenotypes. Mechanistically, ATP11B blocks mitochondrial respiratory function by regulating the chromatin accessibility of KLF4 to mitochondrial respiratory chain complex genes. Simultaneously, it impairs the mitochondrial quality control system, resulting in the accumulation of reactive oxygen species and accelerating neuronal aging. Mitochondrial associated metabolite lactate facilitates histone lactylation modification of ferroptosis and aging key genes Acsl4, Trp53 and Cdkn1a by TEAD YAP complex, thereby promoting transcription. This research elucidates the molecular mechanism by which ATP11B mediates neuronal aging through regulating the iron transport mitochondrial plasticity axis, providing a novel strategy for targeting iron homeostasis to intervene in cognitive decline and neurodegenerative diseases.

大脑衰老伴随认知衰退与神经退行性疾病患病风险升高，神经元衰老（neuronal aging）是连接健康衰老与疾病发生的关键环节。既往研究证实，血脑屏障（blood-brain barrier）完整性的最早受损位点位于海马体，进而引发铁（Fe）的异常蓄积。然而，该过程驱动神经元衰老的具体分子机制仍不明确。本研究通过单细胞与空间转录组学分析，聚焦磷脂翻转酶ATP11B。研究发现，ATP11B缺失可促进室管膜细胞（ependymal cells）向海马神经元的铁转运，激活Hippo信号通路（Hippo signaling pathway），诱导线粒体呼吸功能异常与动力学失衡，最终引发神经元铁死亡（ferroptosis）并加剧衰老表型。机制层面，ATP11B通过调控KLF4对线粒体呼吸链复合体基因的染色质可及性，抑制线粒体呼吸功能；同时损伤线粒体质量控制系统，造成活性氧（reactive oxygen species, ROS）蓄积，加速神经元衰老。此外，线粒体相关代谢物乳酸可通过TEAD-YAP复合物，介导铁死亡与衰老关键基因Acsl4、Trp53、Cdkn1a的组蛋白乳酸化修饰，进而促进其转录。本研究阐明了ATP11B通过调控铁转运-线粒体可塑性轴介导神经元衰老的分子机制，为靶向铁稳态干预认知衰退与神经退行性疾病提供了全新策略。