Alcohol abuse is a major health issue with enormous socio-economic costs. Muscle is one of the major tissues that are negatively impacted by alcohol abuse. While binge drinking causes acute muscle damage such as rhabdomyolysis (muscle fiber dissolution), chronic alcohol abusers suffer from alcoholic muscle disease, such as cardiomyopathy or myopathy. Previous studies in the mammalian muscle showed that habitual alcohol consumption impairs mitochondria function. Along with the unique role of mitochondria in apoptotic cell death, the alcohol-induced impairment in mitochondrial function may explain partially muscle weakness and the atrophy-like symptoms in chronic alcoholic muscle disease. Recent studies have demonstrated that alcohol influences mitochondrial fusion and fission dynamics, which in turn modulates mitochondrial bioenergetics, autophagy and other signaling pathways. However, it is also recognized that chronic alcohol intake causes an array of adverse changes in cellular events and signaling pathways, including reduced mTOR (mechanistic target of rapamycin) signaling and cellular stress responses. One important question that has arisen from these studies is how these altered events and pathways are related to the dynamics of mitochondrial fusion and fission in the context of alcohol toxicity. Are these events and pathways sequential or causal to altered mitochondrial dynamics? Do the cellular events and pathways influence mitochondrial dynamics or vice versa if they occur independently of each other? Understanding their relationship will provide the basis for the identification of effective therapeutic targets. The nematode C. elegans is an excellent model organism that has widely been used to dissect complex cellular events and pathways, such as stress response and apoptotic cell death. We found that the C. elegans muscle exhibited changes in mitochondrial tubular networks upon ethanol exposure. In addition, we observed that chronic alcohol exposure reduced muscle size compared to controls, implicating the involvement of the mTOR signaling pathway that controls cell size and mitochondria biogenesis. Finally, chronic alcohol exposure to C. elegans resulted in the mitochondrial unfolded protein response (UPRmt). The induction of UPRmt by chronic alcohol exposure indicates that alcohol causes mitochondrial protein misfolding. Together, our data showed that alcohol preferentially targets mitochondrial function in muscle. In this exploratory proposal, we will define the inter-relationship between alcohol-induced mitochondrial dynamics and other cellular events or pathways. First, we will define the molecular components responsible for alcohol-mediated muscle mitochondrial fission. Second, we will determine the relationship between UPRmt and mTOR signaling and the alcohol-induced change in mitochondrial dynamics. The successful completion of this project will lead to a better understanding of how alcohol-induced mitochondrial fission interacts with other signaling pathways implicated in alcoholic muscle diseases. Hence, our study will reveal effective therapeutic targets for ameliorating alcohol-induced muscle disease.
Chronic habitual alcohol can cause alcoholic muscle disease, such as cardiomyopathy and myopathy. However, the exact cause of alcoholic muscle disease has not been fully understood. The proposed C. elegans genetic study will help to understand the mechanism that confer alcohol toxicity, thereby providing a basis for the identification of effective therapeutic targets
| Oh, Kelly H; Haney, James J; Wang, Xiaohong et al. (2017) ERG-28 controls BK channel trafficking in the ER to regulate synaptic function and alcohol response in C. elegans. Elife 6: |
| Oh, Kelly H; Kim, Hongkyun (2017) Aldicarb-induced Paralysis Assay to Determine Defects in Synaptic Transmission in Caenorhabditis elegans. Bio Protoc 7: |
| Kim, H; Oh, K H (2016) Protein Network Interacting with BK Channels. Int Rev Neurobiol 128:127-61 |
