Impairment of autophagy: from hereditary disorder to drug intoxication

Abstract

At first, the molecular mechanism of autophagy was unveiled in a unicellular organism Saccharomyces cerevisiae (budding yeast), followed by the discovery that the basic mechanism of autophagy is conserved in multicellular organisms including mammals. Although autophagy was considered to be a non-selective bulk protein degradation system to recycle amino acids during periods of nutrient starvation, it is also believed to be an essential mechanism for the selective elimination of proteins/organelles that are damaged under pathological conditions. Research advances made using autophagy-deficient animals have revealed that impairments of autophagy often underlie the pathogenesis of hereditary disorders such as Danon, Parkinson's, Alzheimer's, and Huntington's diseases, and amyotrophic lateral sclerosis. On the other hand, there are many reports that drugs and toxicants, including arsenic, cadmium, paraquat, methamphetamine, and ethanol, induce autophagy during the development of their toxicity on many organs including heart, brain, lung, kidney, and liver. Although the question as to whether autophagic machinery is involved in the execution of cell death or not remains controversial, the current view of the role of autophagy during cell/tissue injury is that it is an important, often essential, cytoprotective reaction; disturbances in cytoprotective autophagy aggravate cell/tissue injuries. The purpose of this review is to provide (1) a gross summarization of autophagy processes, which are becoming more important in the field of toxicology, and (2) examples of important studies reporting the involvement of perturbations in autophagy in cell/tissue injuries caused by acute as well as chronic intoxication.

Keywords: AMP-activated protein kinase; AMPK; Autophagy; BCL2/adenovirus E1B nineteen kDa protein-interacting protein 3; BNIP3; CYP2E1; Drug; FIP200; FK506-binding protein 12; FKBP12; Hereditary disorder; Keap1; Kelch-like ECH associated protein1; LAMP; LC3; LKB1; MPT; NBR1; NIP3-like protein X; NPC; Niemann–Pick type C; Nix; Nrf2; PI; PINK1; PML/RARA; PTEN-inducible putative kinase protein1; ROS; SOD; TFEB; Toxicology; ULK1/2; cytochrome P450 2E1; focal adhesion kinase family-interacting protein of 200kDa; liver kinase B1; lysosome-associated membrane protein; mTOR; mammalian target of rapamycin; microtuble-associated protein 1 light chain 3; mitochondrial permeability transition; neighbor of Brca1 gene; nuclear factor-erythroid 2-related factor 2; p62/SQSTM1; p62/sequestosome1; phosphatidylinositol; promyelocytic leukemia protein/retinoic acid receptor α; reactive oxygen species; superoxide anion dismutase; transcription factor EB; unc-51-like kinase1/2.