Autophagy facilitates age-related cell apoptosis—a new insight from senile cataract

Abstract

Age-related cell loss underpins many senescence-associated diseases. Apoptosis of lens epithelial cells (LECs) is the important cellular basis of senile cataract resulted from prolonged exposure to oxidative stress, although the specific mechanisms remain elusive. Our data indicated the concomitance of high autophagy activity, low SQSTM1/p62 protein level and apoptosis in the same LEC from senile cataract patients. Meanwhile, in primary cultured LECs model, more durable autophagy activation and more obvious p62 degradation under oxidative stress were observed in LECs from elder healthy donors, compared with that from young healthy donors. Using autophagy-deficiency HLE-B3 cell line, autophagy adaptor p62 was identified as the critical scaffold protein sustaining the pro-survival signaling PKCι-IKK-NF-κB cascades, which antagonized the pro-apoptotic signaling. Moreover, the pharmacological inhibitor of autophagy, 3-MA, significantly inhibited p62 degradation and rescued oxidative stress-induced apoptosis in elder LECs. Collectively, this study demonstrated that durable activation of autophagy promoted age-related cell death in LECs. Our work contributes to better understanding the pathogenesis of senescence-associated diseases.

Biliverdin/Bilirubin Redox Pair Protects Lens Epithelial Cells against Oxidative Stress in Age-Related Cataract by Regulating NF-κB/iNOS and Nrf2/HO-1 Pathways

“…However, when the balance is broken due to excessive intracellular ROS level, glutathione (GSH) depletion, and superoxide dismutase (SOD) downregulation, oxidative stress occurs [ 16 ]. Increased ROS level results in the apoptosis of lens epithelial cells (LECs), which is regarded as the basis of progression for cataract [ 17 ]. Hydrogen peroxide (H 2 O 2 ) is one of the most important ROS in damaged LECs.…”

Differentially expressed gene profiles and associated ceRNA network in ATG7-Deficient lens epithelial cells under oxidative stress

“…Huang J et al also found that autophagy facilitated the apoptosis of HLE-B3 cells under H 2 O 2 stimulation. ( Huang, Yu, He, He, Yang, Chen and Han, 2022 ). By mining the RNA sequencing data, our results showed that the differentially down-regulated genes in autophagy-deficient cells are mostly enriched in GO terms related to cell proliferation and differentiation, such as regulation of hemopoiesis, muscle organ development, and fat cell differentiation, which may suggest a pro-apoptotic function of autophagy.…”

“…Raw counts data of genes were extracted from the RNA-seq dataset of GSE161701 in the NCBI’s GEO database ( https://www.ncbi.nlm.nih.gov/geo/ ). ( Huang, Yu, He, He, Yang, Chen and Han, 2022 ) Specifically, cultured HLE-B3 cells with or without the knockout of the ATG7 gene were respectively treated with or without 200 μM H 2 O 2 for 12 h, thus making four groups of samples for subsequent RNA sequencing (i.e., wild type cells for 0 h and 12 h of stimulation (WT-0h and WT-12 h), and ATG7 knockout cells for 0 h and 12 h of stimulation (KO-0h and KO-12 h), each group with three biological replicates).…”

“…It may suggest a cytoprotective role of autophagy toward LECs under oxidative stress by regulating cell apoptosis, which is quite contradictory to the findings of Huang J et al, whose study revealed autophagy-facilitated apoptosis. ( Huang et al, 2022 ). Therefore, the detailed molecular mechanisms concerning the roles of autophagy in oxidative stress need further explored.…”

Natural Antioxidant Activities of Plants in Preventing Cataractogenesis

“…This results in impaired autophagosome binding to lysosomes, resulting in the accumulation of p62 (a classical receptor of autophagy). This accumulation activates caspases which then increase apoptosis due to the activation of factor-kappa B (NF-κB) [ 90 , 91 ].…”