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Targeting ATP11B-YAP axis repairs mitochondrial function and inhibits neuronal ferroptosis to attenuate age-related
Wenxin Qi1,2, Qian Liu1, Naijun Dong1,3
1School of Life Sciences, Shanghai University, Shanghai, China.
Signal Transduction and Targeted Therapy
|April 19, 2026
Summary
ATP11B deficiency in the brain accelerates neuronal aging by disrupting iron transport and mitochondrial function, leading to ferroptosis. This discovery offers new targets for treating cognitive decline and neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Aging Research
Background:
- Brain aging is linked to cognitive decline and neurodegenerative diseases, with neuronal aging as a primary driver.
- Early blood-brain barrier (BBB) damage in the hippocampus causes abnormal iron (Fe²⁺) accumulation, but downstream mechanisms of neuronal aging are unknown.
Purpose of the Study:
- To investigate the role of phospholipid flippase ATP11B in neuronal aging.
- To elucidate the molecular mechanisms linking iron transport, mitochondrial dysfunction, and aging phenotypes.
Main Methods:
- Single-cell and spatial transcriptomic analyses were employed.
- Investigated the impact of ATP11B deficiency on iron transport, Hippo signaling, mitochondrial function, and gene expression.
- Examined the role of lactate in epigenetic modifications and gene transcription.
Main Results:
- ATP11B deficiency promotes Fe²⁺ transport to hippocampal neurons, activating the Hippo pathway and causing mitochondrial dysfunction and ferroptosis.
- ATP11B regulates mitochondrial respiration by affecting KLF4 chromatin accessibility to mitochondrial respiratory chain genes.
- Lactate promotes histone lactylation of ferroptosis-related genes (Acsl4, Trp53, Cdkn1a) via the TEAD-YAP complex, enhancing neuronal aging.
Conclusions:
- ATP11B mediates neuronal aging through an iron transport-mitochondrial plasticity axis.
- Targeting iron homeostasis presents a novel therapeutic strategy for cognitive decline and neurodegenerative diseases.
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