Mitochondrial injury

Mitochondria generate most of the energy nsed by cells in the form of ATP, which is required to execute aU essential cellnlar fnnctions. When mitochondrial function is impaired, cellnlar fnnction is impaired, which can lead to organ failure and in extreme circumstances to death. Mitochondria have an onter and an inner membrane. The latter harbors the electron transport chain, where ATP is produced. Mitochondria also contain their own DNA, which is small and encodes for 13 proteins and some transfer RNAs. 

The processes of FAO, pyruvate oxidation, and acetyl-Co A oxidation generate the reducing equivalents NADH and FADH2. These are reoxidized by donating electrons to the mitochondrial electron chain, which consists of four 

Most of the electrons donated to the mitochondrial electron transfer chain will react with oxygen to form water. However, a small percentage can leak and cause the formation of superoxide anion radicals, which, if not quickly detoxified, can lead to formation of other radicals and cause oxidative stress. Indeed the mitochondria are thought to be the main producer of ROS, which can damage proteins and nucleic acids and cause cellular damage. Mitochondria contain protective mechanisms that detoxify ROS (and so does the ceU), such as glutathione, superoxide dismutase, peroxiiedoxin, and thioredoxins, but they can be overwhelmed as an insult persists. 

Other mechanisms of drug-induced mitochondrial injury, which have been demonstrated for antivirals and antibiotics. 

Pessayre et al. (2012) and Mehta et al. (2008) describe the effects on mitochondria of more than a hundred compounds that cause liver injury, which are categorized by mechanism of action/target and provide an excellent data resource. 

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Schweinsburg BC, Taylor MJ, Alhassoon OM, Gonzalez R, Brown GG, Ellis RJ, Letendre S, Videen JS, McCutchan JA, Patterson TL, Grant I (2005) Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV-I-) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol ll(4) 356-364... 

It has been suggested that mitochondrial injury was a late and possibly secondary event in mercury nephrotoxicity in rats [224], However, compromised mitochondrial bioenergetic function was later proposed to be one of the earliest intracellular effects of mercuric chloride in the production of nephrotoxicity [226, 227],... 

Botti B, Bini A, Calligaro A, et al. 1986. Decrease of hepatic mitochondrial glutathione and mitochondrial injury induced by 1,2-dibromoethane in the rat in vivo Effect of diethylmaleat pretreatment. Toxicol AppI Pharmacol 83 494-505. 

Dasmahapatra G, Almenara JA, Grant S (2006) Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. Mol Pharmocol 69 288-298... 

Perlmutter, D.H. Liver injury in alpha(l)-antitrypsin deficiency an aggregated protein induces mitochondrial injury (review). J. Clin. Invest. 2002 110 1579-1583... 

Jeon, B.R., Lee, S.M. S-adenosylmethionine protects post-ischemic mitochondrial injury in rat hver. J. Hepatol. 2001 34 395-401... 

It has been suggested that mitochondrial injury may mediate, at least in part, the nephrotoxicity of some p-lactams [67]. Mitochondrial respiration with and uptake of succinate after exposure to toxic doses of cephaloridine, cephaloglycin, or imipenem [98] showed significant reduction of both functions. Cephalexin did not affect either the mitochondrial uptake or respiration with succinate. Depressed mi-... 

Tune BM., Fravert D, Hsu C-Y. Thienamycin nephrotoxicity. Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney. Biochem Pharmacol 1989 38(21) 3779-3783. 

Gordon JA, Gattone VH. Mitochondrial alterations In cisplatin-induced acute renal failure. Am J Physiol 1986 250 F991-8. Brady HR, Kone BC, StronIskI ME, Zeldel ML, Glebisch G, Gullans SR. Mitochondrial Injury an early event In cisplatin-toxicity to renal proximal tubules. Am J Physiol 1990 258 FI 181-7. 

Ong MM, Wang AS, Leow KY, Khoo YM, Boelsterli UA. Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-) mice. Free Radic Biol Med. 2006 40(3) 420-429. 

A feature of the pharmacologic action of azathioprine is its delayed onset, which may take 8-12 weeks to become apparent, possibly due to the slow accumulation of 6-TGN within the cells. The same is not necessarily true for the toxic effects of azathioprine, some of which may occur at any time during treatment (e.g., bone marrow suppression). Azathioprine appears to be a more potent immunosuppressive agent than does 6-MP itself, which may reflect differences in the pharmacodynamics and pharmacokinetics of the two compounds, as well as the relative abundance of different metabolites which are formed after their administration. Studies with hepatocytes have found that azathioprine toxicity involves depletion of reduced glutathione leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was... 

Organellar dysfunction Sarcolemmal injury Sarcoplasmic reticulum dysfunction Mitochondrial injury... 

Rab [87], and Rap [84], For example, statins induce apoptosis at concentrations that suppress the prenylation of Rap la (a 21 kDa GTPase) [84], and Itagaki et al. have shown that this process is accompanied by the redistribution of small G proteins in myoblasts [88], It remains unclear, however, whether the altered prenylation of small G-proteins is necessary and sufficient to produce myopathy in vivo, or whether myocyte apoptosis is first activated by disrupted Ca2+ homeostasis following mitochondrial injury. 

Cationic polystyrene nanosphere toxicity depends on cell-specific endocytic and mitochondrial injury pathways. ACS Nano 2(1) 85-96... 

Perhaps one of the most dramatic examples of hepatic failure and lactic acidosis associated with nucleoside analogues was that which occurred during the course of early clinical trials with an investigational nucleoside analogue fialuridine for treatment of chronic hepatitis B [95]. Seven of fifteen study patients developed progressive liver failure and lactic acidosis. Five of the patients died with severe lactic acidosis two patients underwent emergency liver transplantation and survived. Severe mitochondrial toxicity was proposed as the mechanism for this injury, based in part on the similarity of this presentation to that seen in individuals with inherited disorders of mitochondrial DNA and the presence of histopathological evidence of mitochondrial injury [94, 95]. 

Honkoop, P., et al. (1997). Mitochondrial injury. Lessons from the fialuridine trial. Drug Safety An International Journal of Medical Toxicology and Drug Experience, 17( ), 1—7. 

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