Figure 4: A potential role for TXNIP in the initiation of autophagy/ mitophagy. Macroautophagy or autophagy is a catabolic process of degradation and removal of cytosolic misfolded/aggregated proteins or damaged organelles such as mitochondria (mitophagy, autophagy of mitochondria) by a double membrane [105]. (i) The process of autophagy/ mitophagy may be initiated under starvation by AMP kinase and ATG1/ULK1 or (ii) by Redd1 interaction with 14-3-3 protein to inhibit the mTORC1 pathway, which blocks autophagy. (iii) In addition, JNK2 kinase activation by cellular stresses mediates Bcl2 phosphorylation and releases beclin1 (or ATG6) to initiate autophagy/mitophagy. (iv) Furthermore, oxidation (thiol S-nitrosylation) of specific cysteine residues of nuclear HMGB1 causes its cytosolic translocation and releases beclin1 from bcl2. (v) Similarly, under hypoxia (and chronic hyperglycemia), HIF-1a is stabilized and induces expression of its downstream target BNIP3 (bcl2 interacting protein). BNIP3 then interacts with the beclin1/bcl2 complex releasing beclin1. (vi) Subsequently, autophagy initiation involves ATG5, which modifies and activates microtubule light chain 3B (LC3B) I via lipidation to generate active LC3BII, which initiates double membrane formation. Then, p62 recognizes damaged and ubiquitinflagged cargoes thereby linking them to LC3BII double membrane to autophagosome. LAMP2, a lysosomal membrane protein, mediates fusion of autophagosome and lysosome (autophagolysosome). Lysosomal enzymes, such as cathepsin B and D, degrade the cargo within autophagolysosomes and releases metabolites for reuse. (vii) Mitophagy is critical for mitochondrial homeostasis and cellular survival, especially for differentiated cells such as the RPE and neurons [105,179]. Nonetheless, excess induction of autophagy/ mitophagy induces programmed autophagic cell death involving caspase-3 or independently due to cellular energy collapse.