bims-mideyd 2023-05-28 papers

Issue of 2023‒05‒28
five papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Int J Mol Sci. 2023 May 15. pii: 8763. [Epub ahead of print]24(10):

Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration.

Raji Rajesh Lenin, Yi Hui Koh, Zheting Zhang, Yan Zhuang Yeo, Bhav Harshad Parikh, Ivan Seah, Wendy Wong, Xinyi Su.

Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.

Keywords: age-related macular degeneration; aging; autophagy; clinical trials; mitochondrial dysfunction; retinal pigment epithelium

DOI: https://doi.org/10.3390/ijms24108763

Mol Cells. 2023 May 24.

The Bcl-2/Bcl-xL Inhibitor ABT-263 Attenuates Retinal Degeneration by Selectively Inducing Apoptosis in Senescent Retinal Pigment Epithelial Cells.

Wonseon Ryu, Chul-Woo Park, Junghoon Kim, Hyungwoo Lee, Hyewon Chung.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in elderly individuals. However, the currently used intravitreal injections of anti-vascular endothelial growth factor are invasive, and repetitive injections are also accompanied by a risk of intraocular infection. The pathogenic mechanism of AMD is still not completely understood, but a multifactorial mechanism that combines genetic predisposition and environmental factors, including cellular senescence, has been suggested. Cellular senescence refers to the accumulation of cells that stop dividing due to the presence of free radicals and DNA damage. Characteristics of senescent cells include nuclear hypertrophy, increased levels of cell cycle inhibitors such as p16 and p21, and resistance to apoptosis. Senolytic drugs remove senescent cells by targeting the main characteristics of these cells. One of the senolytic drugs, ABT-263, which inhibits the antiapoptotic functions of Bcl-2 and Bcl-xL, may be a new treatment for AMD patients because it targets senescent retinal pigment epithelium (RPE) cells. We proved that it selectively kills doxorubicin (Dox)-induced senescent ARPE-19 cells by activating apoptosis. By removing senescent cells, the expression of inflammatory cytokines was reduced, and the proliferation of the remaining cells was increased. When ABT-263 was orally administered to the mouse model of senescent RPE cells induced by Dox, we confirmed that senescent RPE cells were selectively removed and retinal degeneration was alleviated. Therefore, we suggest that ABT-263, which removes senescent RPE cells through its senolytic effect, has the potential to be the first orally administered senolytic drug for the treatment of AMD.

Keywords: ABT-263; Bcl-2/Bcl-xL; doxorubicin; senescence; senolytic

DOI: https://doi.org/10.14348/molcells.2023.2188

Mol Med Rep. 2023 Jul;pii: 134. [Epub ahead of print]28(1):

Thioredoxin1 is a target to attenuate diabetes‑induced RPE cell dysfunction in human ARPE19 cells by alleviating oxidative stress.

Hui Qi, Tianhe Liu, Jiasu Liu, Qiufeng Teng, Zhongping Ma, Shengnan Wang, Shihui Wen, Chenghong Zhang, Xiang Ren, Hui Kong, Li Kong.

Diabetes‑induced cell dysfunction of the retinal pigment epithelium (RPE) contributes to the initiation and progression of diabetic retinopathy (DR). Thioredoxin 1 (Trx1) plays a key role in DR. However, the effect and mechanism of Trx1 on diabetes‑induced cell dysfunction of the RPE is not fully understood during DR. In the present study, the effect of Trx1 on this process and its related mechanism were investigated. A Trx1 overexpression cell line, ARPE19‑Trx1/LacZ, was constructed and treated with or without high glucose (HG). Flow cytometry was used to analyze apoptosis of these cells and the mitochondrial membrane potential was analyzed using JC‑1 staining solution. A DCFH‑DA probe was also used to detect the reactive oxygen species (ROS) generation. Western blotting was used to examine the expression of related proteins in ARPE‑19 cells after HG treatment. The results demonstrated that the RPE layer was damaged in clinical samples. ROS formation and RPE cell dysfunction increased after HG treatment in vitro. Besides, the expression of mitochondrial‑mediated apoptosis related proteins (Bax, apoptosis‑inducing factor, cytochrome C, Caspase3 and Caspase9) also increased; however, overexpression of Trx1 attenuated these changes and improved the function of ARPE19 cells. These results indicated that overexpression of Trx1 alleviated diabetes‑induced RPE cell dysfunction in DR by attenuating oxidative stress.

Keywords: apoptosis; diabetic retinopathy; oxidative stress; retinal pigment epithelium; thioredoxin1

DOI: https://doi.org/10.3892/mmr.2023.13021

Biomolecules. 2023 May 13. pii: 832. [Epub ahead of print]13(5):

Role of Complement in the Onset of Age-Related Macular Degeneration.

Niloofar Piri, Henry J Kaplan.

Age-related macular degeneration (AMD) is a progressive degenerative disease of the central retina and the leading cause of severe loss of central vision in people over age 50. Patients gradually lose central visual acuity, compromising their ability to read, write, drive, and recognize faces, all of which greatly impact daily life activities. Quality of life is significantly affected in these patients, and there are worse levels of depression as a result. AMD is a complex, multifactorial disease in which age and genetics, as well as environmental factors, all play a role in its development and progression. The mechanism by which these risk factors interact and converge towards AMD are not fully understood, and therefore, drug discovery is challenging, with no successful therapeutic attempt to prevent the development of this disease. In this review, we describe the pathophysiology of AMD and review the role of complement, which is a major risk factor in the development of AMD.

Keywords: AMD; GA; age-related macular degeneration; complement pathway; drusen; geographic atrophy

DOI: https://doi.org/10.3390/biom13050832

Cell Death Dis. 2023 05 20. 14(5): 334

Klotho prevents transforming growth factor-β2-induced senescent-like morphological changes in the retinal pigment epithelium.

Ha Young Jang, Soo-Jin Kim, Kyu-Sang Park, Jeong Hun Kim.

Degenerative changes of the retinal pigment epithelium (RPE) triggered by transforming growth factor-β2 (TGF-β2) and oxidative stress play a critical role in the progression of age-related macular degeneration (AMD). The expression of α-klotho, an antiaging protein, declines with age, increasing the risk factors for age-related diseases. Here, we investigated the protective effects of soluble α-klotho on TGF-β2-induced RPE degeneration. The morphological changes induced by TGF-β2, including epithelial-mesenchymal transition (EMT), were attenuated in the mouse RPE by the intravitreal injection (IVT) of α-klotho. In ARPE19 cells, EMT and morphological alterations by TGF-β2 were attenuated by co-incubation with α-klotho. TGF-β2 decreased miR-200a accompanied by zinc finger e-box binding homeobox1 (ZEB1) upregulation and EMT, all of which were prevented by α-klotho co-treatment. Inhibitor of miR-200a mimicked TGF-β2-induced morphological changes, which were recovered by ZEP1 silencing, but not by α-klotho, implying the upstream regulation of α-klotho on miR-200a-ZEP1-EMT axis. α-Klotho inhibited receptor binding of TGF-β2, Smad2/3 phosphorylation, extracellular signal-regulated protein kinase 1/2 (ERK1/2)-a mechanistic target of rapamycin (mTOR) activation and oxidative stress via NADPH oxidase 4 (NOX4) upregulation. Furthermore, α-klotho recovered the TGF-β2-induced mitochondrial activation and superoxide generation. Interestingly, TGF-β2 upregulated α-klotho expression in the RPE cells, and genetic suppression of endogenous α-klotho aggravated TGF-β2-induced oxidative stress and EMT. Lastly, α-klotho abrogated senescence-associated signaling molecules and phenotypes induced by long-term incubation with TGF-β2. Hence, our findings indicate that the antiaging α-klotho plays a protective role against EMT and degeneration of the RPE, demonstrating the therapeutic potential for age-related retinal diseases, including the dry type of AMD.

DOI: https://doi.org/10.1038/s41419-023-05851-8