Although more commonly referred to as “the powerhouses of the cell” due to their energy-producing abilities, mitochondria also play an important role in regulating cell health. These important structures can be damaged by alcohol consumption, which can cause them to break down and release their DNA, proteins, and lipids, collectively known as “damage-associated molecular patterns” (DAMPs).
The rupture of mitochondria and the release of DAMP causes widespread inflammation, which can lead to cell damage in the liver, contributing to liver disease and even cancer. To avoid this, cells have a process, called mitophagy, to selectively remove damaged mitochondria before they cause inflammation. However, the processes that regulate mitophagy and its long-term effects on liver health under conditions of alcohol exposure are less well understood.
To better understand how alcohol damages mitochondria and how this leads to mitophagy, researchers at the Medical University of South Carolina (MUSC) used an advanced imaging technique to study changes in mitochondrial function in the liver of mice exposed to alcohol. Their findings, published online March 16 in the journal Autophagy, demonstrated that alcohol exposure causes a specific type of mitochondrial damage, called depolarization. In a completely new discovery, they discovered that it is this depolarization that signals to the cell that the mitochondria are damaged and thus causes the mitophagic machinery to activate to remove the damaged mitochondria before they can cause damage.
“Mitochondria can become a ticking time bomb, and we need to contain them,” said John J. Lemasters, MD, Ph.D., director of the Center for Cell Death, Injury and Regeneration and GlaxoSmithKline Distinguished Endowed Chair in the College of Pharmacy. .
Previously, researchers noted that after acute or short-term exposure to alcohol — such as that which occurs during a single night of heavy drinking — mitochondria are damaged but can recover. When alcohol is processed in the liver, the toxic molecule acetaldehyde (AcAld) is produced, which can damage cells. Mitochondria help in the removal of AcAld, but they are damaged or depolarized in the process, requiring their removal. Intact mitochondria are replicated and cells continue to function properly.
So, as summarized by Lemasters, who originally coined the term mitophagy, damage in the form of depolarization is beneficial because it helps to quickly remove ethanol, especially acetaldehyde, a toxic byproduct.
However, in the chronic or long-term conditions of alcohol exposure – such as that which occurs after years of alcohol consumption as seen in alcohol dependence – the continuous cycle of mitochondrial damage followed by their elimination becomes pathogenic, because less healthy mitochondria remain each time. The constant removal of so many injured mitochondria leads to problems such as mitochondrial depletion syndrome, in which an insufficient amount of ATP or energy is produced. Other cellular functions also begin to decline.
The current study determined that mitochondrial injury, specifically depolarization, initiates mitophagy to prevent damaged mitochondria from accumulating in cells. Blocking depolarization after ethanol exposure also blocks mitophagy, preventing mitochondrial depletion.
“No mitochondria are better than bad mitochondria,” Lemasters said.
These so-called “bad” mitochondria, which have been damaged by toxic AcAld, can release their toxic DAMPs into cells if not segregated and degraded. Zhi Zhong, MD, Ph.D., a professor in the Department of Drug Discovery and Biomedical Sciences and lead author of this study, mentioned that DAMPs could be useful in future studies.
“Mitochondrial DAMPs are associated with liver cell damage and can be used as a biomarker to see a correlation between disease severity and liver damage,” Zhong said.
Directly inhibiting depolarization is likely to be difficult. Therefore, the team investigated methods to help mitochondria process AcAld so that fewer mitochondria are injured by depolarization and degraded. One method is to stimulate the activity of an enzyme that processes AcAld using a drug called Alda-1. While treatment with this drug was successful in reducing the number of injured mitochondria in mouse livers, Alda-1 showed significant generalized toxicity in clinical trials and is therefore a poor candidate for clinical use. However, Alda-1’s success in reducing mitochondrial damage, which may be beneficial in the long term, provides the foundation for developing better drugs and methods to prevent mitochondrial damage in the liver.
Interestingly, the questions posed in this study could only be answered using animal models. Indeed, in cell culture models, mitochondrial depolarization after acute alcohol treatment does not occur. So the researchers used a relatively new technology called intravital multiphoton microscopy, which is a sophisticated way to obtain detailed images of cellular structures in living animals. Combined with innovative mouse models that make fluorescently colored cellular components, which track their health and interaction, previously unanswered questions about the consequences of alcohol exposure on mitochondria have been investigated. .
The MUSC team was able to determine that both acute and chronic alcohol exposure leads to mitochondrial damage in the form of depolarization. Mitochondrial depolarization directly initiates mitophagy to degrade damaged mitochondria. While acute injury can be repaired by replication of healthy, undamaged mitochondria, chronic alcohol exposure causes repeated degradation of mitochondria, leading to mitochondrial depletion, inflammation, fibrosis, cirrhosis, and ultimately, liver disease.
Determining how alcohol damages mitochondria may lead to new methods for diagnosing liver disease at an early stage and developing more effective treatments. In addition to providing more detailed background science on mitochondrial function and triggers of mitophagy, this manuscript lays the groundwork for future studies on the development of new therapies for alcoholic and non-alcoholic liver disease.