Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high‐dose pharmaceutical‐grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high‐dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1⁻ mouse model of adrenomyeloneuropathy. High‐dose biotin restored redox homeostasis driven by NRF‐2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP‐1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High‐dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high‐dose biotin of relevance for neurodegenerative and metabolic disorders.

中文翻译：

---

高剂量生物素可在肾上腺脑白质营养不良模型中恢复氧化还原平衡、能量和脂质稳态以及轴突健康。

生物素是调节能量代谢的羧化酶的重要辅助因子。最近，高剂量药物级生物素 (MD1003) 被证明可以改善一部分慢性进行性多发性硬化患者的临床参数。为了深入了解作用机制，我们研究了高剂量生物素在由氧化损伤和生物能量衰竭引起的慢性轴突病遗传模型Abcd1 ^{- 中}的功效^。肾上腺脊髓神经病小鼠模型。高剂量生物素恢复由 NRF-2、线粒体生物发生和 ATP 水平驱动的氧化还原稳态，并逆转轴突死亡和运动障碍。此外，我们发现了可能由异常 SREBP-1c/mTORC1 信号驱动的脊髓脂质合成和降解转录程序的协调失调。这导致运动神经元中甘油三酯水平和脂滴增加。高剂量生物素使 mTORC1 的过度活化正常化，从而恢复脂质稳态。这些结果揭示了与神经退行性疾病和代谢疾病相关的高剂量生物素的作用机制。