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Alcohol and mitochondria: A dysfunctional relationship
Reported by Jules Levin
  This study (Gastroenterology June 2002, Vol 122, Number 7) reports that alcohol and perhaps aging can damage the mitochondria. We know that studies in HIV suggest that mitochondrial damage may be associated with fat loss (lipoatrophy). This study suggests that alcohol use may contribute. Perhaps, excessive alcohol use should be considered as a parameter in lipodystrophy studies. Genetic predisposition, diabetes, elevated lipids, aging, alcohol, HIV, HAART immune reconstitution, and NRTI use may all play a role in lipoatrophy.
Mitochondria are intimately involved in the generation of and defense against reactive oxygen species (ROS). Mitochondria are themselves targets of oxidative stress and also contribute to mechanisms by which oxidative stress-related signals control cell fate. Ethanol promotes oxidative stress, both by increasing ROS formation and by decreasing cellular defense mechanisms. These effects of ethanol are prominent in the liver, the major site of ethanol metabolism in the body. The question remains to what extent this contributes to ethanol-dependent tissue damage or the susceptibility of cells to other stressors. In this review, we consider how mitochondrial actions of ethanol influence oxidative stress management of liver cells. Mitochondrial electron transport constitutes the major intracellular source of ROS, and ethanol treatment imposes conditions that promote ROS formation by mitochondria, the effects of which may be enhanced by a decrease in mitochondrial oxidative stress defenses. A significant target of ethanol-related increases in oxidative stress is mitochondrial DNA. Ethanol-induced damage to mitochondrial DNA, if not adequately repaired, impairs mitochondrial function, which further increases oxidative stress in the cell, leading to a vicious cycle of accumulating cell damage that is more apparent with advancing age. Uncontrolled mitochondrial formation of ROS promotes the inappropriate activation of the mitochondrial permeability transition, increasing the sensitivity of cells to other pro-apoptotic or damage signals. In combination with ethanol-induced defects in mitochondrial function, these alterations may promote both apoptotic and necrotic cell death in response to otherwise benign or beneficial challenges and contribute to the onset or progression of alcohol-induced liver diseases.
Mansouri et al. reported a marked loss of mouse hepatic mtDNA (by 50% of total mtDNA) within hours after an acute dose of ethanol (5 g/kg by gavage). If ethanol treatment would depress any of the components of the replication machinery or inhibit their activities, either directly or by ethanol-induced oxidative stress, mtDNA depletion may result. advancing age may contribute to mtDNA depletion in response to challenges, such as ethanol treatment. Because mtDNA is required for the maintenance of the cell's bioenergetic capacity, this may ultimately impair the cellular energy supply.
There is now considerable evidence that ethanol treatment disturbs the balance of pro- and anti-apoptotic factors to enhance the susceptibility of cells and tissues to apoptotic stimuli, and that this involves facilitation of MPT activation.
There is considerable evidence that aging further enhances ethanol-induced cell damage through mechanisms that involve the MPT. Multiple copies of mtDNA are present in all mitochondria in a cell, and a certain level of damage to mtDNA can be tolerated, as long as intact copies are available. However, there is considerable literature that damage to mtDNA increases with advanced age, and the "mitochondrial theory of aging" suggests that accumulation of defective mtDNA would impair cellular energy metabolism, placing a limit on the life span of the cell (and by extension the organism). If mitochondria lack effective mechanisms to repair or dispose of excess oxidative damage, the additional production of ROS resulting from ethanol intake could exacerbate this damage, with potentially serious consequences. Alternatively, depending on the chemical nature of the changes in mtDNA, rather than accumulating, damaged mtDNA may be degraded more rapidly and the integrity of the mtDNA pool may depend on its repletion.
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