■线粒体动力学在其质量控制中起着重要作用,受损的线粒体成分通过自噬被清除。在糖尿病性视网膜病变中,线粒体融合酶,mitofusin2(Mfn2),下调,线粒体动力学受到干扰,导致线粒体去极化和功能失调。我们的目的是研究Mfn2的抑制机制,及其在去除受损线粒体中的作用,糖尿病视网膜病变。
■使用人视网膜内皮细胞,确定了高葡萄糖(20mM)对Mfn2的GTP酶活性及其乙酰化的影响。Mfn2在去除受损线粒体中的作用通过调节其乙酰化得到证实,或通过Mfn2过表达,自噬-自溶酶体形成和线粒体自噬通量。
■高葡萄糖抑制GTP酶活性并增加Mfn2的乙酰化。抑制乙酰化,或Mfn2过表达,减弱GTP酶活性和线粒体片段化的降低,并增加了受损线粒体的去除。在糖尿病小鼠中观察到类似的现象;沉默酶1(脱乙酰酶)的过表达改善了糖尿病诱导的视网膜Mfn2抑制,并促进了受损线粒体的去除。
■Mfn2的乙酰化在糖尿病视网膜病变的线粒体稳态中具有双重作用,它抑制Mfn2的GTP酶活性并增加线粒体片段化,也会损害受损线粒体的去除。因此,保护Mfn2活性应维持线粒体稳态并抑制糖尿病性视网膜病变的发展/进展。
Mitochondrial dynamic plays a major role in their quality control, and the damaged mitochondrial components are removed by autophagy. In diabetic retinopathy, mitochondrial fusion enzyme,
mitofusin 2 (Mfn2), is downregulated and mitochondrial dynamic is disturbed resulting in depolarized and dysfunctional mitochondria. Our aim was to investigate the mechanism of inhibition of Mfn2, and its role in the removal of the damaged mitochondria, in diabetic retinopathy.
Using human retinal endothelial cells, effect of high glucose (20mM) on the GTPase activity of Mfn2 and its acetylation were determined. Role of Mfn2 in the removal of the damaged mitochondria was confirmed by regulating its acetylation, or by Mfn2 overexpression, on autophagosomes- autolysosomes formation and the mitophagy flux.
High glucose inhibited GTPase activity and increased acetylation of Mfn2. Inhibition of acetylation, or Mfn2 overexpression, attenuated decrease in GTPase activity and mitochondrial fragmentation, and increased the removal of the damaged mitochondria. Similar phenomenon was observed in diabetic mice; overexpression of sirtuin 1 (a deacetylase) ameliorated diabetes-induced inhibition of retinal Mfn2 and facilitated the removal of the damaged mitochondria.
Acetylation of Mfn2 has dual roles in mitochondrial homeostasis in diabetic retinopathy, it inhibits GTPase activity of Mfn2 and increases mitochondrial fragmentation, and also impairs removal of the damaged mitochondria. Thus, protecting Mfn2 activity should maintain mitochondrial homeostasis and inhibit the development/progression of diabetic retinopathy.