线粒体生物发生在糖尿病性视网膜病变持续进展相关代谢记忆中的作用及其受硫辛酸的调节。
Role of mitochondria biogenesis in the metabolic memory associated with the continued progression of diabetic retinopathy and its regulation by lipoic acid.
机构信息
Kresge Eye Institute, Wayne State University, Detroit, Michigan 48201, USA.
出版信息
Invest Ophthalmol Vis Sci. 2011 Nov 11;52(12):8791-8. doi: 10.1167/iovs.11-8203.
PURPOSE
Termination of hyperglycemia does not arrest the progression of diabetic retinopathy, and retinal mitochondrial DNA (mtDNA) remains damaged, resulting in a continuous cycle of mitochondrial dysfunction. This study is to investigate the role of mitochondria biogenesis (regulated by nuclear mitochondrial signaling) in the metabolic memory phenomenon.
METHODS
Mitochondria DNA copy number, functional integrity, and biogenesis (peroxisome proliferator-activated receptor-γ coactivator-1α [PGC1], nuclear respiratory factor 1 [NRF1], mitochondrial transcriptional factor [TFAM]) were analyzed in the retina from streptozotocin-diabetic rats maintained in poor or good control for 12 months (PC and GC respectively), or in PC for 6 months followed by 6 months of GC (Rev). The effect of direct inhibition of superoxide on prior insult was investigated by supplementing lipoic acid (LA) during their 6 months of GC (R+LA). Binding of TFAM with chaperones (heat shock proteins 70 and 60, Hsp70 and Hsp60 respectively) was quantified by coimmunoprecipitation. The key parameters and the number of mitochondria (by transmission electron microscopy and fluorescence microscopy) were confirmed in isolated retinal endothelial cells.
RESULTS
Six months of GC in the rats in Rev group did not provide any benefit to diabetes-induced decreased mtDNA copy number, increased gene transcripts of PGC1, NRF1, and TFAM, and decreased mitochondrial TFAM. The binding of TFAM with the chaperones remained subnormal. Supplementation of LA (R+LA), however, had a significant beneficial effect on the impaired mitochondria biogenesis, and also on the continued progression of diabetic retinopathy. Similar results of reversal of high glucose insult were observed in isolated retinal endothelial cells.
CONCLUSIONS
Dysregulated mitochondria biogenesis contributes to the metabolic memory, and supplementation of GC with therapies targeted in modulating mitochondria homeostasis has potential in helping diabetic patients retard progression of retinopathy.
目的
高血糖的终止并不能阻止糖尿病视网膜病变的进展，并且视网膜线粒体 DNA（mtDNA）仍然受损，导致线粒体功能障碍的持续循环。本研究旨在探讨线粒体生物发生（受核线粒体信号调节）在代谢记忆现象中的作用。
方法
分析链脲佐菌素诱导的糖尿病大鼠视网膜中线粒体 DNA 拷贝数、功能完整性和生物发生（过氧化物酶体增殖物激活受体-γ 共激活因子-1α [PGC1]、核呼吸因子 1 [NRF1]、线粒体转录因子 [TFAM]），这些大鼠分别维持在较差或较好的控制 12 个月（PC 和 GC 分别），或在 PC 维持 6 个月后再维持 6 个月的 GC（Rev）。通过在其 6 个月的 GC 期间补充硫辛酸（LA）来研究直接抑制超氧化物对先前损伤的影响（R+LA）。通过共免疫沉淀定量 TFAM 与伴侣（热休克蛋白 70 和 60，分别为 Hsp70 和 Hsp60）的结合。通过透射电子显微镜和荧光显微镜确认分离的视网膜内皮细胞中的关键参数和线粒体数量。
结果
Rev 组大鼠的 6 个月 GC 并没有为糖尿病引起的 mtDNA 拷贝数减少、PGC1、NRF1 和 TFAM 的基因转录增加以及线粒体 TFAM 减少提供任何益处。TFAM 与伴侣的结合仍然不正常。然而，LA 的补充（R+LA）对受损的线粒体生物发生有显著的有益作用，并且对糖尿病视网膜病变的持续进展也有作用。在分离的视网膜内皮细胞中也观察到了逆转高葡萄糖损伤的类似结果。
结论
失调的线粒体生物发生导致代谢记忆，并且用靶向调节线粒体动态平衡的治疗方法补充 GC 具有帮助糖尿病患者延缓视网膜病变进展的潜力。
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