Lutein upregulates the PGC-1α, NRF1, and TFAM expression by AMPK activation and downregulates ROS to maintain mtDNA integrity and mitochondrial biogenesis in hyperglycemic ARPE-19 cells and rat retina
Lutein upregulates the PGC-1α, NRF1, and TFAM expression by AMPK activation and downregulates ROS to maintain mtDNA integrity and mitochondrial biogenesis in hyperglycemic ARPE-19 cells and rat retina
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DOI：
10.1002/bab.1821
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发表时间：
2019-10-24
影响因子：
2.8
通讯作者：
Vallikannan, Baskaran
中科院分区：
文献类型：
--
作者：
Nanjaiah, Hemalatha;Vallikannan, Baskaran
高血压（HG）影响细胞器，包括视网膜中的线粒体，其通过下调核转录因子过氧化物酶体增殖物激活受体-γ共激活因子-1（PGC-1 α）和线粒体转录因子A（TFAM）来减少线粒体生物合成。线粒体功能障碍与糖尿病视网膜病变（DR）有关。据报道，类胡萝卜素可调节HG的线粒体生物合成。本研究的目的是探索叶黄素、氧化叶黄素（叶黄素经UV氧化后纯化）和药物二甲双胍对HG诱导的ARPE-19细胞和大鼠视网膜中线粒体生物合成的作用。结果显示，与对照组相比，HG组大鼠视网膜和ARPE-19细胞对叶黄素和氧化型叶黄素的摄取量明显增加。此外，与对照组和二甲双胍组相比，叶黄素和氧化叶黄素增强了AMPK磷酸化和腺苷酸信号分子TFAM（蛋白质表达）的活化以及PGC-1 α、TFAM和核呼吸因子1（负责线粒体生物合成）的mRNA表达，同时沿着HG中活性氧的降低。烟酰胺腺嘌呤二核苷酸脱氢酶亚基mt-ND 1，mt-ND 4，mt-ND 6和细胞色素C的较高mRNA表达也被证明有助于维持mtDNA的完整性。总之，发现叶黄素和氧化叶黄素在HG下的ARPE-19细胞和大鼠视网膜中增加线粒体生物合成，这可能是由于AMPK磷酸化的上调。最后，叶黄素和氧化叶黄素可能为改善汞诱导的DR提供治疗基础。
Hyperglycemia (HG) affects cellular organelle including mitochondrion in retina that diminishes mitochondrial biogenesis by downregulation of nuclear transcription factors peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1 alpha) and mitochondrial transcription factor A (TFAM). Mitochondrial dysfunction has been linked to diabetic retinopathy (DR). Carotenoids reported to modulate mitochondrial biogenesis in HG. Aim of the study was to explore the role of lutein, oxidized lutein (purified upon UV oxidation of lutein) and drug metformin, on mitochondrial biogenesis in HG-induced ARPE-19 cells and rat retina. Results showed higher uptake of lutein and oxidized lutein in ARPE-19 cells and rat retina of HG group than the control groups. Further, lutein and oxidized lutein augmented the AMPK phosphorylation and activation of mitochondrion signaling molecule TFAM (protein expression) and mRNA expression of PGC-1 alpha, TFAM, and nuclear respiratory factor 1 (responsible for mitochondria biogenesis) along with lowered reactive oxygen species in HG compared with control and metformin groups. Higher mRNA expression of nicotinamide adenine dinucleotide dehydrogenase subunits mt-ND1, mt-ND4, mt-ND6, and cytochrome C that aid maintenance of mtDNA integrity was also evidenced. To conclude, lutein and oxidized lutein found to upsurge mitochondrial biogenesis in ARPE-19 cells and rat retina under HG, which may be due to upregulation of AMPK phosphorylation. Finally, lutein and oxidized lutein may provide a therapeutic basis to ameliorate HG-induced DR.