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.