bims-mideyd 2023-03-26 papers

Redox Biol. 2023 Mar 15. pii: S2213-2317(23)00076-9. [Epub ahead of print]62 102675

DAPL1 deficiency in mice impairs antioxidant defenses in the RPE and leads to retinal degeneration with AMD-like features.

Xiaoyin Ma, Huaicheng Chen, Shuhui Jian, Junhao He, Youjia Liu, Shuxian Han, Lifu Chang, Pingping Li, Ying-Ao Chen, Xiaoyan Liu, Xiaojuan Hu, Yu Chen, Ling Hou.

The decreased antioxidant capacity in the retinal pigment epithelium (RPE) is the hallmark of retinal degenerative diseases including age-related macular degeneration (AMD). Nevertheless, the exact regulatory mechanisms underlying the pathogenesis of retinal degenerations remain largely unknown. Here we show in mice that deficiencies in Dapl1, a susceptibility gene for human AMD, impair the antioxidant capacity of the RPE and lead to age-related retinal degeneration in the 18-month-old mice homozygous for a partial deletion of Dapl1. Dapl1-deficiency is associated with a reduction of the RPE's antioxidant capacity, and experimental re-expression of Dapl1 reverses this reduction and protects the retina from oxidative damage. Mechanistically, DAPL1 directly binds the transcription factor E2F4 and inhibits the expression of MYC, leading to upregulation of the transcription factor MITF and its targets NRF2 and PGC1α, both of which regulate the RPE's antioxidant function. When MITF is experimentally overexpressed in the RPE of DAPL1 deficient mice, antioxidation is restored and retinas are protected from degeneration. These findings suggest that the DAPL1-MITF axis functions as a novel regulator of the antioxidant defense system of the RPE and may play a critical role in the pathogenesis of age-related retinal degenerative diseases.

Keywords: AAV; AMD; MITF; Oxidative stress; Pigment cell

DOI: https://doi.org/10.1016/j.redox.2023.102675

iScience. 2023 Mar 17. 26(3): 106270

MFN1 augmentation prevents retinal degeneration in a Charcot-Marie-Tooth type 2A mouse model.

Saba Shahin, Bin Lu, Yueqin Zhou, Hui Xu, Jason Chetsawang, Robert H Baloh, Shaomei Wang.

Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss, color-vision defects, and progressive loss of visual acuity. We used a well-established transgenic mouse model of CMT2A with R94Q mutation on MFN2 gene (MFN2 R94Q ) to investigate the functional and morphological changes in retina. We documented extensive vision loss due to photoreceptor degeneration, retinal ganglion cell and their axonal loss, retinal secondary neuronal and synaptic alternation, and Müller cell gliosis in the retina of MFN2 R94Q mice. Imbalanced MFN1/MFN2 ratio and dysregulated mitochondrial fusion/fission result in retinal degeneration via P62/LC3B-mediated mitophagy/autophagy in MFN2 R94Q mice. Finally, transgenic MFN1 augmentation (MFN2 R94Q :MFN1) rescued vision and retinal morphology to wild-type level via restoring homeostasis in mitochondrial MFN1/MFN2 ratio, fusion/fission cycle, and PINK1-dependent, Parkin-independent mitophagy.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience; Sensory neuroscience

DOI: https://doi.org/10.1016/j.isci.2023.106270

Proc Natl Acad Sci U S A. 2023 Mar 28. 120(13): e2217576120

Peroxisome proliferator-activated receptor-α (PPARα) regulates wound healing and mitochondrial metabolism in the cornea.

Wentao Liang, Li Huang, Amy Whelchel, Tian Yuan, Xiang Ma, Rui Cheng, Yusuke Takahashi, Dimitrios Karamichos, Jian-Xing Ma.

Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mitochondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochondrial function, we found that Peroxisome Proliferator-Activated Receptor-α (PPARα) expression was downregulated in diabetic human corneas. Even without diabetes, global PPARα knockout mice and corneal epithelium-specific PPARα conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPARα agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific PPARα transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPARα agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of PPARα, suggesting a PPARα-dependent mechanism. These findings suggest that downregulation of PPARα plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes.

Keywords: PPARα; cornea; epithelium; mitochondria; wound healing

DOI: https://doi.org/10.1073/pnas.2217576120

Int J Ophthalmol. 2023 ;16(3): 348-353

Expression levels of ROS and Atg proteins in the vitreous in rhegmatogenous retinal detachment.

Nan Huang, Xue-Yan Gao, Jin-Ping Li, Xing Lu, Hua-Mei Zhu, Kai Dong.

AIM: To detect the concentrations of reactive oxygen species (ROS), transient receptor potential mucin-1 (TRPML1), and autophagy-related (Atg) proteins (LC3-I, LC3-II, and Beclin1) in vitreous humor of patients with simple rhegmatogenous retinal detachment (RRD).
METHODS: RRD patients enrolled as the RRD group, and patients with idiopathic macular hole (IMH) and idiopathic macular epiretinal membrane (IMEM) were enrolled as control group. The levels of ROS, TRPML1, LC3-I, LC3-II, and Beclin1 in vitreous humor of patients in the RRD and control groups were detected by enzyme-linked immunosorbent assay (ELISA).
RESULTS: The RRD group included 28 eyes 28 patients and had a higher concentration of ROS in vitreous humor (631.86±18.05 vs 436.34±108.22 IU/mL, P<0.05). The ROS level in patients with a wide retinal detachment (RD) extent (RD range ≥1/2) was higher than that with a narrow RD extent (RD range<1/2, P<0.05). ROS concentration was negatively correlated with RD time (r=-0.46, P=0.01). The expression levels of LC3-I and Beclin1 significantly decreased in RRD (P<0.05), but there were no correlations with the RD time, RD extent, or macular involvement.
CONCLUSION: In eyes with RRD, the concentration of ROS in vitreous humor increases and the expression levels of Atg proteins decrease, reflecting possibly that autophagy is inhibited.

Keywords: autophagy-related proteins; reactive oxygen species; retinal detachment; vitreous body

DOI: https://doi.org/10.18240/ijo.2023.03.03