Scientists from the UNC Greensboro Center for Translational Biomedical Research made unprecedented connections between alcohol-induced hepatic zinc deficiency and a defect in the mitochondria in their American Journal of Physiological: Gastrointestinal and Liver Physiology paper: “Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency.”
These findings come just about a year after the same group published detailed findings on zinc levels in the mitochondria before and after alcohol exposure, and it provides vital clues toward preventing early stages of alcohol-induced liver disease from progressing to lethal stages.
A defect in the mitochondrial electron transport chain (ETC) is bad news for a cell’s survival chances. The ETC, made up of multiple respiratory complexes, is the key to energy generation in the mitochondria, an organelle famously referred to as the “powerhouse of the cell.” On the other hand, zinc deficiency has been linked to a variety of health problems, and some studies have observed zinc being involved in antioxidant defenses. Previous studies have shown that zinc supplementation in mice with chronic exposure to alcohol reversed reactive oxygen species (ROS) production in the liver.
Results from the 2015 study from the UNC Greensboro scientists located on the NC Research Campus in Kannapolis about 90 miles southeast from their main campus, proved that levels of zinc are especially abundant in the mitochondria compared with other subcellular compartments, but zinc levels lowered drastically after exposure to alcohol. In the current study, UNC Greensboro researchers set their sights on determining once and for all whether or not a link between alcohol-induced hepatic zinc deficiency and a defect in the mitochondrial ETC existed, as well as show if the ETC defect contributed to the production of ROS.
During their experiments, researchers exposed live rats to chronic alcohol consumption, looking for effects in the liver, mitochondria, mitochondrial respiratory complexes, and mitochondrial DNA expression. Additionally, they tested the impact of zinc deficiency directly on isolated human liver carcinoma cells.
They found that ROS accumulated both in the liver and in the mitochondria after chronic alcohol consumption, and while chronic alcohol feeding decreased the expression of complexes I, III, IV, and V, complex II was left unhindered. Later, they discovered that complex IV is by far the most sensitive to oxidative damage in response to alcohol consumption, while complex II is the most resistant.
Reduced expression in the complexes of the ETC led to the decrease in production of energy in the form of ATP. Additionally, the researchers saw a reduction in hepatic NRF1, a key nuclear transcription factor in the respiratory chain gene expression, in response to alcohol consumption.
When looking at zinc deficiency and isolated cells, they also saw reduced expression in the same four mitochondrial respiratory complexes as well as decreased expression of mitochondrial biogenesis regulators, including NRF1.
“ROS buildup and zinc deficiency could be the cause for each other,” explained Zhanxiang Zhou co-director of the UNC Greensboro center. “Alcohol is first metabolized to acetaldehyde in the endoplasmic reticulum by CYP2E1; this process generates ROS which can mobilize zinc from zinc proteins, leading to inactivation of zinc proteins as well as reduction of cellular zinc levels.”
Alcoholic liver disease can take the form of multiple pathological spectrums, from steatosis to hepatitis, cirrhosis, and even carcinoma. Researchers believe that the alcohol-induced generation of ROS promotes the progression of a “simple steatosis” to dangerous carcinoma, and understanding how zinc deficiency is involved helps scientists get one step closer to preventing carcinoma from developing.
By Kara Marker, NCRC Marketing