Zhou Jie, Terluk Marcia R, Orchard Paul J, Cloyd James C, Kartha Reena V
Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA.
Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, 425 East River Parkway, Minneapolis, MN 55455, USA.
Biomedicines. 2021 Dec 3;9(12):1826. doi: 10.3390/biomedicines9121826.
The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether -acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1-100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.
由于过氧化物酶体功能障碍导致的饱和超长链脂肪酸（VLCFA，≥C22:0）积累会引发X连锁肾上腺脑白质营养不良（ALD）中的氧化应激和神经退行性变。在神经支持细胞中，产生髓磷脂的少突胶质细胞对VLCFA的有害作用最为敏感。在此，我们对VLFCA诱导的线粒体功能障碍和细胞死亡进行了表征，并研究了抗氧化剂N-乙酰半胱氨酸（NAC）是否能预防细胞毒性。我们将小鼠少突胶质细胞（158N）暴露于二十六烷酸（C26:0，1 - 100μM）中24小时，并测量活性氧（ROS）和细胞死亡情况。低浓度的C26:0（≤25μM）对细胞存活有轻微影响，ROS或总谷胱甘肽（GSH）浓度无变化。然而，对用C（26:）0（25μM）处理的细胞的线粒体状态分析显示线粒体GSH（mtGSH）耗竭，内膜电位降低。这些结果表明VLCFA扰乱线粒体膜电位，导致ROS积累、氧化应激和细胞死亡。我们进一步测试了NAC（500μM）是否能预防VLCFA对用C26:0处理的少突胶质细胞的线粒体特异性影响。我们的结果表明，NAC可提高少突胶质细胞中的mtGSH水平和线粒体功能，表明其在治疗ALD及相关疾病方面具有潜在用途。
