Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.
Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.
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作者：
Xiong ZM;Choi JY;Wang K;Zhang H;Tariq Z;Wu D;Ko E;LaDana C;Sesaki H;Cao K
Hutchinson-Gilford早衰症(HGPS)是一种致命的早衰病，由LMNA基因的单核苷酸突变引起。以前的报道主要集中在HGPS细胞的核表型上，但线粒体作为正常衰老的关键因素，其潜在作用尚不清楚。使用高分辨率显微镜分析，我们发现HGPS成纤维细胞中线粒体肿胀和碎裂的比例显著增加，线粒体迁移率显著降低。值得注意的是，线粒体生物发生的中央调节因子pGC-1α的表达被孕激素抑制。为了挽救线粒体缺陷，我们用线粒体靶向抗氧化剂亚甲蓝(MB)处理HGPS细胞。我们的分析表明，MB处理不仅减轻了线粒体缺陷，而且挽救了HGPS细胞中标志性的核异常。进一步的分析表明，MB处理释放了核膜上的孕激素，挽救了核周异染色质的丢失，并纠正了HGPS细胞中错误调控的基因表达。综上所述，这些结果证明了线粒体功能障碍在HGPS细胞过早衰老表型的形成中所起的作用，并提示MB是一种有前景的HGPS治疗方法。
Hutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.