The LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors that provide cellular stress protection. Their suppression dampens the autophagy response, lowers mitochondrial respiration, and elevates mitochondrial ROS, and their inducible overexpression protects against rotenone toxicity in human iPSC-derived mDANs in vitro. Significantly, we show that LMX1A and LMX1B stability is in part regulated by autophagy, and that these transcription factors bind to multiple ATG8 proteins. Binding is dependent on subcellular localization and nutrient status, with LMX1B interacting with LC3B in the nucleus under basal conditions and associating with both cytosolic and nuclear LC3B during nutrient starvation. Crucially, ATG8 binding stimulates LMX1B-mediated transcription for efficient autophagy and cell stress protection, thereby establishing a novel LMX1B-autophagy regulatory axis that contributes to mDAN maintenance and survival in the adult brain.

中文翻译：

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ATG8 依赖性 LMX1B 自噬串扰塑造人中脑多巴胺能神经元弹性

LIM 同源域转录因子 LMX1A 和 LMX1B 是中脑多巴胺能神经元 (mDAN) 分化和存活的重要介质。在这里，我们证明 LMX1A 和 LMX1B 是提供细胞应激保护的自噬转录因子。它们的抑制会抑制自噬反应，降低线粒体呼吸，并提高线粒体 ROS，它们的诱导性过度表达可在体外保护人 iPSC 衍生的 mDAN 免受鱼藤酮毒性。值得注意的是，我们发现 LMX1A 和 LMX1B 的稳定性部分受自噬调节，并且这些转录因子与多个 ATG8 蛋白结合。结合取决于亚细胞定位和营养状态，LMX1B 在基础条件下与细胞核中的 LC3B 相互作用，并在营养饥饿期间与细胞质和细胞核 LC3B 结合。至关重要的是，ATG8 结合刺激 LMX1B 介导的转录，以实现有效的自噬和细胞应激保护，从而建立一个新的 LMX1B 自噬调节轴，有助于成人大脑中 mDAN 的维持和存活。