Liver mitochondria improve, increase after chronic alcohol feeding in mice

The liver is a vital organ, playing a major role in metabolism and detoxification in the body. Overconsumption of alcohol has long been tied to liver diseases such as fatty liver, alcoholic hepatitis and cirrhosis, but how the substance damages the organ is not fully understood. USC research published in the Dec. 7, 2012, issue of the Journal of Biological Chemistry, a peer-reviewed scientific journal, suggests that mitochondria play an important role in the liver's response to the metabolic stress caused by alcohol intake. If scientists observe the same results in human mitochondria, it could help pinpoint targets for therapy.

"The liver has to adapt quickly to various toxins and drugs to meet the demands we place on the body," said Derick Han, Ph.D., assistant professor of research medicine at the Keck School of Medicine of USC and first author of the study. "We've found that mitochondrial plasticity -- the mitochondria's ability to change -- is probably central to the liver's response to alcohol intake. This gives us a better understanding of how the liver works and how it adapts to stress."

Mitochondria are cellular organelles that generate most of the cell's energy; they have been implicated in certain neurological disorders and have been tied to aging. The metabolism of oxygen by the mitochondria normally generates reactive oxygen species, or free radicals, which in excess can be highly damaging to cells.

"In the short term, it looks like mitochondria adapt to metabolize alcohol better, but as they increase in number and use more oxygen to help metabolize that alcohol, it could be harmful to the body," Han said.

Han and his team of scientists fed alcohol to mice over four weeks, isolated the liver mitochondria and measured levels of respiration and changes in the mitochondrial structure. They found significant increases in oxygen consumption by mice fed the alcohol in comparison to control mitochondria as early as one week after feeding. Changes were greater and more extensive with higher alcohol intake.

USC co-authors include Maria Ybanez, Heather Johnson, Jeniece McDonald, Lusine Mesropyan, Harsh Sancheti, Lily Dara and Enrique Cadenas. The study's senior investigators include Hidekazu Tsukamoto, director of the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis, and Neil Kaplowitz, director of the USC Research Center for Liver Diseases. The study was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (grants AA016911, AA14428, and AA011999).

A team led by Kaplowitz is set to launch a four-year clinical trial in 2013 to study two potential new treatments for alcoholic hepatitis. Han hopes to collect data from that trial to further examine mitochondrial function in human livers exposed to alcohol.