Abstract：
The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients\' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
摘要：
过氧化物酶体病肾上腺脑白质营养不良（X-ALD）是由超长链脂肪酸（VLCFAs）的转运蛋白丢失引起的，ABCD1.过量的VLCFA会破坏对轴突维持至关重要的基本稳态功能，包括氧化还原代谢，糖酵解和线粒体呼吸。由于线粒体功能和形态交织在一起，我们着手研究线粒体动力学在X-ALD模型中的作用。使用定量3D透射电子显微镜，我们揭示了Abcdl-小鼠皮质脊髓轴突的线粒体片段化。在患者成纤维细胞中，过量的VLCFA通过DRP1的氧化还原依赖性磷酸化触发线粒体片段化(DRP1S616)。肽P110对DRP1驱动的裂变的阻断有效地保留了线粒体形态。此外，在X-ALD的秀丽隐杆线虫模型中，DRP1的mRNA抑制不仅可以防止线粒体断裂，而且可以保护轴突健康。强调DRP1作为潜在的治疗靶点。患者CSF中循环无细胞mtDNA水平升高使这种脑白质营养不良与原发性线粒体疾病一致。我们的发现强调了过氧化物酶体功能障碍之间复杂的相互作用，X-ALD中的线粒体动力学和轴突完整性，阐明治疗干预的潜在途径。
