Mitochondrial abnormalities

Even in Alzheimer s disease (AD), the possible involvement of a weak excitotoxic process cannot be ruled out. Indeed, mitochondrial abnormalities (such as cytochrome oxidase alterations) [36, 37] and increased levels of markers of oxidative stress [38] have been reported in AD. This has been the rationale for testing the NMDA antagonist memantine in Alzheimer s dementia [39]. 

Ong, M.M., Latchoumycandane, C. and Boelsterli, U.A. (2007) Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicological Sciences,... 

Boelsterli, U.A. and Lim, P.L. (2007) Mitochondrial abnormalities-a link to idiosyncratic drug hepatotoxicity Toxicology and Applied Pharmacology,... 

Results from this study showed that SOD activity was not affected by acute ADR treatment. A second finding was that acute ADR toxicity did not promote cardiac lipid peroxidation. However, it was observed that mitochondrial lipid peroxidation was highest in mice fed diets low in both antioxidants. Ultrastructural examination revealed mitochondrial abnormalities in cardiac tissue from ADR-treated animals (Figures 3 and 4). There were large vacuoles within the mitochondria and condensation of the inner and outer membranes of the mitochondria. The ultrastructural effects of ADR treatment were most severe in the low E, Mn-deficient mice. It is reasonable to suggest that a higher than normal level of lipid peroxidation may predispose the animal to tissue damage from ADR. Consistent with this concept, Meyers et al. (34) have reported that pretreatment with supplemental vitamin E can reduce the toxicity of ADR in mice. 

Mitochondrial abnormalities ATP synthase alpha chain VDAC-1 Sultana et al. (2(X)6b)... 

Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain mechanistic implications. Ann Neurol 57 695-703... 

Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, lohnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, lones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer s disease. 1 Neurosci 21 3017-3023... 

Zhou XW, Tanila H, Pei JJ (2008b) Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Abeta overproduction. FEES Lett 582 159—164 Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, Hirai K, Smith MA (2006) Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis 9 147-153... 

American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision). American Psychiatric Association, New york, NY Blass JP (2006) Concise chnical pharmacology CNS therapeutics. McGraw-Hill, New york, NY Bowen DM, Smith CB, White P, Davison AN (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99 459-496 Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain mechanistic implications. Ann Neurol 57 695-703 Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13 36-64... 

Chemicals that damage mitochondrial structure, enzymes, or DNA synthesis can disrupt beta oxidation of hpids and oxidative energy production within hepatocytes. Prolonged interruption of beta oxidation leads to micro-vesicular steatosis which can progress to macrovesicular steatosis. This sequence of events has been noted with alcoholic and nonalcoholic steatohepatitis. The role of mitochondria has been extensively studied with nonalcoholic fatty hver disease, a major issue in human medicine. Alcoholic steatosis and other forms of hepatic steatosis have been linked to impairment of ATP homeostasis and mitochondrial abnormalities have been reported in a growing body of hterature. 

Von Ruecker AA, Bertele R, Harms HK. Calcium metabolism and cystic fibrosis mitochondrial abnormalities suggest a modification of the mitochondrial membrane. Pediatr Res 18 (1984) 594-9. 

Mitochondrial Myopathy - Some degree of mitochondrial abnormality has been reported in several diseases of muscle. These morphological changes might be a response to some non-specific abnormal metabolic state of skeletal... 

Engel, A. G., and Dale, A. J. D., Autophagic glycogenosis of late onset with mitochondrial abnormalities Light and electron microscopic observations. Mayo Clin. Proc. 43, 233-279 (1968). 

Hanson et al. [105] found increased amounts of 3a,7a,12a-trihydroxy-5 -choIes-tan-26-oic acid, 3a,7a-dihydroxy-5]3-chotestan-26-oic acid, and varanic acid in the urine of 3 infants with Zellweger s syndrome [106]. The same observation was reported by Mathis et al. in 2 other patients with this syndrome [107]. Furthermore, Monnens et al. found an increased amount particularly of the trihydroxy t Uc acid and also of the dihydroxy C27 bite acid in bile and serum from 2 infants with this syndrome [108]. The increased concentrations of higher bile acids may be explained by mitochondrial abnormalities in the liver of patients with Zellweger s syndrome [109]. More recent studies indicate that the occurrence of Q- i acids is related to the absence of peroxisomes in this disease (cf. Chapter 9). 

Boelsterli UA, Lim PL (2007) Mitochondrial abnormalities - a link to idiosyncratic drag hepatotoxicity Toxicol Appl Pharmacol 220(1) 92—107... 

VPA. Histologically, microvesicular steatosis induced by 4-en-VPA is accompanied by ultrastructural changes characterized by myeloid bodies, hpid vacuoles and mitochondrial abnormalities. An enhanced excretion of Cg to Cio dicarboxylic acids by patients and rats indicates an interference with mitochondrial P-oxidation as an important pathogenesis. If the normal pathway of fatty acid oxidation is disrupted by VPA, it results in reduced ketone body formation and decrease of free coenzyme-A (CoA) in the liver. Especially, decreased CoA would limit the activities of one or more enzymes in the pathway of fatty acid oxidation. 

Bubber, P, V. Haroutunian, G. Fisch et al. Mitochondrial abnormalities in Alzheimer brain Mechanistic implications. 57(5), 2(X)5 695-703. 

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