Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage

Abstract

Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.

New Treatment Strategies for Alcohol-Induced Heart Damage

“…The presence of sustained systemic inflammatory response also increases alcohol-induced heart damage [22,27,62], and must be controlled to avoid increased heart-damage.…”

Disrupted ER‐to‐Golgi trafficking underlies anti‐HIV drugs and alcohol‐induced cellular stress and hepatic injury

“…The incomplete protections through targeting the ER suggest that although ER stress is involved in alcohol and drug-induced hepatotoxicity, there are other drug and alcohol-targeted cellular components that either enhance or are upstream of the ER stress response. (21) …”

“…Abnormal Golgi morphologies occur when the protein load and modifications exceed Golgi capacity. (21–23) For instance, enlargement or hypertrophy of the Golgi has been observed in human liver due to amyloidosis, toxic hepatitis, and other conditions, including drug-induced cholestasis and malnutrition. (24) Atrophy or degeneration occurs during starvation, viral hepatitis, and choline or protein deficiency.…”

“…(27) There is also an adaptive Golgi stress response (GSR) that involves Golgi resident protein 60 (GCP60), heat shock protein 47 (HSP47), and transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) to cope with disrupted homeostasis of the Golgi. (21,22) However, persistent stress on the Golgi disturbs metabolism in the liver, and dysfunction of the Golgi apparatus is associated with various stress-induced liver injuries. (21–28) The role that the Golgi plays in drug and alcohol-induced ER stress and what underlying molecular mechanism links Golgi dysfunction with the ER stress response and injury are not known.…”

“…(21,22) However, persistent stress on the Golgi disturbs metabolism in the liver, and dysfunction of the Golgi apparatus is associated with various stress-induced liver injuries. (21–28) The role that the Golgi plays in drug and alcohol-induced ER stress and what underlying molecular mechanism links Golgi dysfunction with the ER stress response and injury are not known. In this study, we observed that antivirals induced Golgi morphological changes in cultured liver cells and mouse livers.…”