Mitochondrial damage

Mitochondria-associated toxicities, such as pancreatitis, are frequently demonstrated in HlV/HCV-coinfected individuals, and may significantly influence treatment options (de Mendoza and Soriano 2005). Yet, no cell culture or animal models have been developed to predict nucleoside-induced pancreatitis. Nevertheless, an association of HCV replication and mitochondrial DNA depletion in primary human lymphocytes obtained from HIV/HCV-coinfected individuals under concomitant administration of HCV and HIV medications was demonstrated by de Mendoza and coworkers (de Mendoza et al. 2007). They claimed that the use of HCV medication together with certain antiretroviral agents seemed to enhance mitochondrial damage due to a synergistic deleterious interaction between the anti-HCV and anti-HIV drugs. In contrast, an improvement in mitochondrial content with effective... 

Antiretroviral toxic neuropathy Any stage Subacute rarely acute with lactic acidosis Distal sensory loss and neuropathic pain Toxic neuropathy mitochondrial damage... 

A.J. Kowaltowski and A.E. Vercesi, Mitochondrial damage induced by conditions of oxidative stress. Free Radic. Biol. Med. 26, 463-471 (1999). 

Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates. Necrosis is characterized by marked dysregulation of ion homeostasis resulting in cell swelling, dilation of mitochondria and the ER and the formation of vacuoles in the cytoplasm [33], Proteases play important roles in the degradation of cells during necrosis. In contrast to apoptosis, where caspases are the key death proteases, calpains and lysosomal proteases (cathepsins B and D, in particular) are major players in necrosis. Caspases may be activated in response to mitochondrial damage and... 

Bendotti, C., Calvaresi, N., Chiveri, L. etal. Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. /. Neurol. Sci. 191 25-33,2001. 

Given that bile acids, particularly deoxycholic acid, can damage DNA, one might expect bile acids to demonstrate mutagenic effects. This might be particularly apparent in eukaryotic cells that could sustain mitochondrial damage or release NO via the mechanisms described above. 

Cyclodextrinyl ditelluride has been recognized as an excellent glutathione peroxidase mimic, revealed in die mitochondrial damage system induced by ferrous sulphate/ascor-bate. ... 

Qu B., Q.-T. Li, K.P. Wong, T.M.C. Tan, and B. Halliwell (2001). Mechanisms of clofibrate hepatoxicity Mitochondrial damage and oxidative stress in hepatocytes. Free Radical Biology and Medicine 31 659-669. 

The major secondary events are changes in membrane structure and permeability, changes in the cytoskeleton, mitochondrial damage, depletion of ATP and other cofactors, changes in Ca2+ concentration, DNA damage and poly ADP-ribosylation, lysosomal destabilization, stimulation of apoptosis, and damage to the endoplasmic reticulum. 

At low levels of mitochondrial damage, removal of damaged mitochondria by lysosomes rescues the cell. If this is overwhelmed then apoptosis occurs triggers such as cytochrome c (see below) start the apoptotic process. If most or all mitochondria are damaged, then the depletion of ATP is so extensive that the apoptotic process is not possible (ATP is required for the process), and the cell undergoes necrosis. 

Figure 6.17 The intracellular signaling leading to apoptosis initiated by mitochondrial damage, DNA damage, or stimulation of Fas or TNF-1 receptors. For full explanation see text.

Secondary events result from primary events, for example, changes in membrane structure/permeability, mitochondrial damage, and lysosomal destabilization. Tertiary events are final observable manifestations, for example, fatty change and phospholipidosis, apoptosis, blebbing, and necrosis. 

These drugs can also cause mitochondrial damage, dysfunction of fat metabolism and liver failure. 

However, in vitro studies in hepatoma cells showed that lysosmal damage precedes the DNA and mitochondrial damage. 

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