Impaired mitochondrial function

Augustin, W. et al.. Beta-carotene cleavage products induce oxidative stress by impairing mitochondrial functions brain mitochondria are more sensitive than liver mitochondria, Free Rad. Biol. Med., 33, S326, 2002. 

Siems, W, Wiswedel, I, Salerno, C, Crifo, C, Augustin, W, Schild, L, Langhans, CD, and Sommerburg, O, 2005. Beta-carotene breakdown products may impair mitochondrial functions—Potential side effects of high-dose beta-carotene supplementation. J Nutr Biochem 16, 385-397. 

Both the time of analysis and experimental design may affect the results. An explanation for the increase in adenylates under the conditions of our experiment is still needed. Since both ATP alone and total adenylate concentrations have increased, it does not appear that a shift in phosphorylation can account for the increases. The decrease in photosynthesis and increase in adenylates occur during the same time period and both factors return to normal after 21 hr. From previous research we know that the photosynthetic levels of ozonated pinto bean foliage decrease immediately after ozone exposure even when symptoms do not develop ( ). This does not hold true for the adenylate or respiration responses. Therefore, it appears that the ozone-initiated increase in adenylates is not correlated directly to the photosynthetic response. The increase in respiration persists when adenylate content and photosynthetic rates have returned to normal. Impaired mitochondrial function appears to be a secondary response more closely related to symptom development. 

It is important to mention at this point that most drugs have more than one mechanism of impairing mitochondrial function. For example, troglitazone not only inhibits the OXPHOS complexes IV and V but also induces MPT. 

HI based on their findings of incomplete recovery of NTP. However, as the cerebral metabolic rate of oxygen did not correlate with any metabolic changes, they concluded impaired mitochondrial function could not be the only factor. 

Hyperlactatemia and metabolic acidosis are adverse effects of linezolid that could be related to impaired mitochondrial function. Linezolid-induced lactic acidosis occurred in a 70-year-old man during the first 7 days of... 

Heales SJ, Davies SE, Bates TE, Clark JB. 1995. Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration. Neurochem Res 20 31-38. 

Hanzel, C.E., Verstraeten, S.V. (2005). Thallium induces hydrogen peroxide generation hy impairing mitochondrial function. Toxicol. Appl. Pharmacol. 216 485-92. 

Researchers have recently found evidence that links impaired mitochondrial function to the spread of cancer cells.11 Found in cells, mitochondria convert food molecules into energy. Without adequate energy, our cells can find... 

Peroxynitrite is a powerful oxidant that, as a charged species, is poorly diffusible from the intramitochondrial space. When ONOO is produced in excess, as in inflammation and in ischemia-reperfusion, there is tyrosine nitration of the mitochondrial proteins. Mitochondrial levels of 2-5 nM ONOO" have been estimated for the mitochondrial matrix under physiological conditions [12,22], and levels above 20-30 nM are considered cytotoxic. The existence of a stable low ONOO concentration is indicated by the detection of nitrotyrosine in normal mitochondria [36]. At high levels, ONOO overwhelms the reducing reactions, and oxidation and nitration of lipids and proteins may impair mitochondrial function. The whole syndrome of mitochondrial dysfunction appears driven by excess NO and ONOO. This mitochondrial syndrome, observed in ischemia-reperfusion, inflammation, and aging [37-39] is characterized by decreased rates of state 3 respiration and ATP synthesis, decreased respiratory controls and membrane potential, increased rates of state 4 respiration, and increased mitochondrial size and fragility. 

At present oral doses, tetracycline and its derivatives produce mild hepatic steatosis in humans at worst. However, fatal cases of microvesicular steatosis have occurred in the past, usually after 4—10 days of intravenous administration of high doses of either tetracycline or diverse tetracycline derivatives (Zimmerman 1978). Predisposing conditions (Zimmerman 1978) included preexisting renal failure, which decreases tetracycline elimination, or pregnancy, which can impair mitochondrial function. 

Some drugs impair mitochondrial function through a combination of mechanisms. A good example is valproic acid, which inhibits mitochondrial fatty acid oxidation by sequestering coenzyme A (a cofactor necessary for fatty acid activation and... 

When a drug being developed causes frequent adverse effects in humans it rarely reaches the market. As a result, when marketed dmgs are used at recommended therapeutic doses, very few cases of DILI occur. Except for cases from overdoses, most cases of DILI can be considered idiosyncratic. The reasons for the unique susceptibility of a few individuals are not completely understood. However, both variations in drug metabolism/excretion and the presence of medical conditions that also impair mitochondrial function can be involved. 

Another example of the increased susceptibility of patients with certain viral infections for dmg-induced mitochondrial dysfunction is the increased hepatotox-icity of highly active antiretroviral therapy (HAART) in HIV/HBV or HCV coinfected patients (Sulkowski et al. 2002 Wit et al. 2002). Certain viral proteins such as the HCV core protein or the HBV X protein disturb mitochondrial function (Rahmani et al. 2002 Korenaga et al. 2005 Piccoli et al. 2007), and, together with cytokines, could impair mitochondrial function and make HBV- or HCV-coinfected subjects more susceptible to HAART-induced liver toxicity. 

Drugs and other associated medical conditions that also impair mitochondrial function may have an additive effect to damage mitochondria and trigger liver injury. 

The presence of diverse comorbid factors that also impair mitochondrial function (such as inborn mitochondrial cytopathies, inborn (3-oxidation defects, viral infections, obesity-associated NASH, or pregnancy) may play an important role in the idios3tncratic occurrence of these drag-induced adverse effects. 

Boulos M, Astiz ME, Barua RS et al. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med 2003 31 353-8. 

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