An update on the bridging factors connecting autophagy and Nrf2 antioxidant pathway.

Macroautophagy/autophagy is a lysosome-dependent catabolic pathway for the degradation of intracellular proteins and organelles. Autophagy dysfunction is related to many diseases, including lysosomal storage diseases, cancer, neurodegenerative diseases, cardiomyopathy, and chronic metabolic diseases, in which increased reactive oxygen species (ROS) levels are also observed. ROS can randomly oxidize proteins, lipids, and DNA, causing oxidative stress and damage. Cells have developed various antioxidant pathways to reduce excessive ROS and maintain redox homeostasis. Treatment targeting only one aspect of diseases with autophagy dysfunction and oxidative stress shows very limited effects. Herein, identifying the bridging factors that can regulate both autophagy and antioxidant pathways is beneficial for dual-target therapies. This review intends to provide insights into the current identified bridging factors that connect autophagy and Nrf2 antioxidant pathway, as well as their tight interconnection with each other. These factors could be potential dual-purpose targets for the treatment of diseases implicated in both autophagy dysfunction and oxidative stress.

Upregulation of the TFEB-mediated lysosome function relieves 4-Hydroxynonenal-Induced apoptosis.

4-Hydroxynonenal (4-HNE), the most toxic end-product of lipid peroxidation formed during oxidative stress, has been implicated in many diseases including neurodegenerative diseases, metabolic diseases, myocardial diseases, cancer and age-related diseases. 4-HNE can actively react with DNA, proteins and lipids, causing rapid cell death. The accumulation of 4-HNE leads to induction of autophagy, which clears damaged proteins and organelles. However, the underlying mechanism of 4-HNE-regulated autophagy is still not known. Transcriptional factor EB (TFEB) is a master regulator of lysosomal and autophagic functions, which we show here that TFEB is activated by 4-HNE. 4-HNE induces TFEB nuclear translocation and activated TFEB then upregulates the expression of genes required for autophagic and lysosomal biogenesis and function. Reactive oxygen species and Ca2+ are required in this process and TFEB activity is required for 4-HNE-mediated lysosomal function. Most importantly, genetic inhibition of TFEB (TFEB-KO) exacerbates 4-HNE-induced cell death, suggesting that TFEB is essential for cellular adaptive response to 4-HNE-induced cell damage. Hence, targeting TFEB to promote autophagic and lysosomal function may represent a promising approach to treat neurodegenerative and metabolic diseases in which 4-HNE accumulation has been implicated.