Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines.
Microvesicular steatosis occurs in conditions characterized by severe impairment of the mitochondrial beta-oxidation process, due to genetic and/or acquired causes. Drugs and some endogenous compounds can sequester coenzyme A (aspirin, valproic acid), inhibit mitochondrial beta-oxidation enzymes (tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine), or inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhexestrol), while female sex hormones have complex, but moderate, effects on mitochondrial structure and function. Other substances impair mitochondrial DNA transcription (interferon-alpha) or mitochondrial DNA replication (dideoxynucleosides), while alcohol abuse might accelerate the normal oxidative aging of mitochondrial DNA. When beta-oxidation is severely impaired, fatty acids, which are poorly oxidized by mitochondria, are mainly esterified into triglycerides, but there is a residual increase in non-esterified fatty acids. Triglycerides (possibly emulsified by a rim of non-esterified fatty acids) accumulate as small vesicles. Impairment of energy production, and the mitochondrial and general toxicity of both non-esterified fatty acids and dicarboxylic acids, may contribute to liver failure, coma and death in severe forms. Although milder forms of microvesicular steatosis have a good short-term prognosis, they can lead to chronic lipid peroxidation and the development of steatohepatitis lesions. Investigational molecules with a carboxylic group or a protonatable amine, or those which might interfere with mitochondrial DNA, should be screened for possible mitochondrial effects.
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Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 24, Hôpital Beaujon, Clichy, France.
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D000818:Animals; D003065:Coenzyme A / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D004272:DNA, Mitochondrial / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005234:Fatty Liver / Q000378:metabolism*; D006728:Hormones / Q000502:physiology; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000150:complications; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction
D016207:Cytokines; D004272:DNA, Mitochondrial; D006728:Hormones; D000431:Ethanol; D003065:Coenzyme A