4.7 Article

Impaired mitochondrial dynamics and removal of the damaged mitochondria in diabetic retinopathy

Journal

FRONTIERS IN ENDOCRINOLOGY
Volume 14, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2023.1160155

Keywords

diabetic retinopathy; mitochondria; mitofusin; mitophagy; mitochondrial dynamics; retina

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In diabetic retinopathy, the downregulation of mitochondrial fusion enzyme Mfn2 leads to disruption of mitochondrial dynamics and dysfunction. This study found that increased acetylation of Mfn2 inhibits its GTPase activity, causes mitochondrial fragmentation, and impairs removal of damaged mitochondria. Therefore, protecting Mfn2 activity could maintain mitochondrial homeostasis and inhibit the development/progression of diabetic retinopathy.
IntroductionMitochondrial 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. MethodsUsing 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. ResultsHigh 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. ConclusionsAcetylation 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.

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