bims-mideyd 2022-05-08 papers

Issue of 2022‒05‒08
three papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Exp Eye Res. 2022 Apr 28. pii: S0014-4835(22)00175-0. [Epub ahead of print] 109095

Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis.

Meng-Yuan Zhang, Lingpeng Zhu, Xun Bao, Tian-Hua Xie, Jiping Cai, Jian Zou, Wenjuan Wang, Shun Gu, Yan Li, Hong-Ying Li, Yong Yao, Ting-Ting Wei.

Diabetic retinopathy (DR) is a potentially blinding complication resulting from diabetes mellitus (DM). Retinal vascular endothelial cells (RMECs) dysfunction occupies an important position in the pathogenesis of DR, and mitochondrial disorders play a vital role in RMECs dysfunction. However, the detailed mechanisms underlying DR-induced mitochondrial disorders in RMECs remain elusive. In the present study, we used High glucose (HG)-induced RMECs in vitro and streptozotocin (STZ)-induced Sprague-Dawley rats in vivo to explore the related mechanisms. We found that HG-induced mitochondrial dysfunction via mitochondrial Dynamin-related protein 1(Drp1)-mediated mitochondrial fission. Drp1 inhibitor, Mdivi-1, rescued HG-induced mitochondrial dysfunction. Protein Kinase Cδ (PKCδ) could induce phosphorylation of Drp1, and we found that HG induced phosphorylation of PKCδ. PKCδ inhibitor (Go 6983) or PKCδ siRNA reversed HG-induced phosphorylation of Drp1 and further mitochondrial dysfunction. The above studies indicated that HG increases mitochondrial fission via promoting PKCδ/Drp1 signaling. Drp1 induces excessive mitochondrial fission and produces damaged mitochondrial, and mitophagy plays a key role in clearing damaged mitochondrial. Our study showed that HG suppressed mitophagy via inhibiting LC3B-II formation and p62 degradation. 3-MA (autophagy inhibitor) aggravated HG-induced RMECs damage, while rapamycin (autophagy agonist) rescued the above phenomenon. Further studies were identified that HG inhibited mitophagy by down-regulation of the PINK1/Parkin signaling pathway, and PINK1 siRNA aggravated HG-induced RMECs damage. Further in-depth study, we propose that Drp1 promotion of Hexokinase II (HK-II) separation from mitochondria, thus inhibiting HK-II-PINK1-mediated mitophagy. In vivo, we found that intraretinal microvascular abnormalities (IRMA), including retinal vascular leakage, acellular capillaries, and apoptosis were increased in STZ-induced DR rats, which were reversed by pretreatment with Mdivi-1 or Rapamycin. Altogether, our findings provide new insight into the mechanisms underlying the regulation of mitochondrial homeostasis and provide a potential treatment strategy for Diabetic retinopathy.

Keywords: Diabetic retinopathy; Drp1; Mitochondrial fission; Mitophagy; PINK1

DOI: https://doi.org/10.1016/j.exer.2022.109095

Eur J Pharmacol. 2022 Apr 29. pii: S0014-2999(22)00240-0. [Epub ahead of print] 174979

Astaxanthin ameliorates hyperglycemia induced inflammation via PI3K/Akt-NF-κB signaling in ARPE-19 cells and diabetic rat retina.

Rajasekar Janani, Vinothkumar Anitha, Peethambaran Divya, Muzaffar Chonche, Vallikannan Baskaran.

Astaxanthin has been reported to possess anti-inflammatory effect but the exact mechanism in protecting the retinal pigment epithelial (RPE) cells is not clear. Hence, we hypothesized that astaxanthin could protect RPE by inhibiting ROS-mediated inflammation. The purpose of this study is to understand the retinal protective mechanism of astaxanthin in modulating hyperglycemia (HG) induced inflammation in ARPE-19 cell and diabetic rat retina. ARPE-19 cells were treated with 30 mM glucose to induce hyperglycemia whereas diabetes was induced in rats with streptozotocin followed by astaxanthin treatment. The level of oxidative stress markers, antioxidant enzyme activity, inflammatory markers (NF-κB, TNF-α, ICAM-1), signaling mediators (PI3K, p-Akt) and nuclear translocation of NF-κB were analyzed in ARPE-19 cells and rat retina. HG-mediated ROS generation and lipid peroxidation were declined upon astaxanthin treatment in ARPE-19 cells. Similarly, astaxanthin treatment found to reduce the elevated levels of nitric oxide, protein carbonyl, and lipid peroxides in diabetic group. Astaxanthin restored the activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione transferase in serum and retina of diabetic rats. NF-κB, TNF-α, and ICAM-1 levels were higher in HG-treated ARPE-19 cells and diabetic retina compared to control group, whereas astaxanthin treatment lowered their expression. PI3K and p-Akt were higher in high glucose treated ARPE-19 cells and diabetic retina. NAC, LY294002 and PDTC treatment resulted in reduced nuclear translocation of NF-κB and decreased expression of inflammatory markers in HG treated ARPE-19 cells. Thus, we conclude that astaxanthin protected the retinal cells from HG-induced inflammation by modulating the NF-κB through ROS-PI3K/Akt signaling cascade.

Keywords: Astaxanthin; Hyperglycemia; Inflammation; NF-κB; Oxidative stress; PI3K/Akt

DOI: https://doi.org/10.1016/j.ejphar.2022.174979

Invest Ophthalmol Vis Sci. 2022 May 02. 63(5): 5

Photoreceptor Manifestations of Primary Mitochondrial Optic Nerve Disorders.

Yin-Hsi Chang, Eugene Yu-Chuan Kang, Pei-Kang Liu, Sarah R Levi, Hung-Hsuan Wang, Yun-Ju Tseng, Go Hun Seo, Hane Lee, Lung-Kun Yeh, Kuan-Jen Chen, Wei-Chi Wu, Chi-Chun Lai, Laura Liu, Nan-Kai Wang.

Purpose: To compare the manifestations of photoreceptors (PRs) in three hereditary optic neuropathies affected by primary mitochondrial dysfunction and discuss whether the retinal ganglion cells (RGCs) or the PRs are preferentially affected.Methods: A retrospective analysis of patients with genetically confirmed diagnoses of optic neuropathies associated with mitochondrial dysfunction was performed. This cohort included Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy type 1 (OPA1), and optic atrophy type 13 (OPA13). Patient chart evaluations included clinical characteristics, best-corrected visual acuity (BCVA), fundus photography, spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG), and visual evoked potential data.
Results: This analysis included seven patients with LHON, six with OPA1, and one with OPA13 from a tertiary medical center. Thirteen of the 14 individuals were male. The average BCVA at diagnosis was 20/285 and 20/500 in the right and left eyes, respectively. Five of the seven patients with LHON, and three of the six patients with OPA1 also showed a mild amplitude reduction or delayed latency on light-adapted ERG and 30-Hz flicker responses; however, SD-OCT imaging did not show correlated PR abnormalities. Notably, a 7-year follow-up of a patient with OPA13 revealed degeneration of RGCs prior to the degeneration of PRs. Follow-up data also demonstrated continuous loss of cone outer segment tips on SD-OCT imaging.
Conclusions: RGCs are, in general, affected by mitochondrial dysfunction, whereas variable PR dysfunction exists in patients with LHON and OPA1, especially with respect to the cone responses. Involvement of PRs is particularly evident in OPA13 after RGC degenerations.

DOI: https://doi.org/10.1167/iovs.63.5.5