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Aging, The Molecular Concepts

2.10. MnSOD DEFICIENT MICE

Having established the importance of mitochondrial ATP deficiency in degenerative disease, the relevance of mitochondrially generated ROS was explored. Unlike the ANT1 -/- mice, the MnSOD -/- mice died at about 8 days of age of a dilated cardiomyopathy together with an exceptionally fatty liver. Biochemical analysis revealed severe reductions in SDH and mitochondrial aconitase, and a partial reduction in heart NADH dehydrogenase, all enzymes containing iron-sulfur (Fe-S) centers (14, 85, 86). No increase in malondialdehyde (MDH) was detected in heart or brain and no significant increase was found in mtDNA rearrangements by LX-PCR (86). Hence, inactivation of the MnSOD results in lethal cardiomyopathy, presumably due to acute ROS toxicity. By contrast, mice lacking the cytosolic Cu/ZnSOD (87) or the extracellular Cu/ZnSOD (88) are fully viable. Hence, the mitochondria are clearly the primary source and target of toxic O2. To further establish that the lethal cardiomyopathy of the MnSOD -/- animals was due to ROS toxicity, we attempted to compensate for the defect by administering the exogenous SOD mimic MnTBAP (manganese 5, 10, 15, 20- tetrakis (4-benzoic acid) porphyrin). Intraperitoneal injection of MnTBAP, starting at 3 days after birth, resulted in the complete rescue of the cardiomyopathy and extension of the mean survival time from 8.3 days to 16.4 days. Furthermore, MnTBAP substantially reduced the fat accumulation in the liver. Hence, excessive mitochondria O2- production does shut down mitochondrial energy production, resulting in dilated cardiomyopathy and death (89).

Unfortunately, MnTBAP cannot cross the blood brain barrier. Consequently, the neurons of the MnTBAP treated animals continue to be exposed to high levels of mitochondrial superoxide anion. This results in the animals developing a complex array of movement disorders at about two weeks of age. These include repetitive behaviors such as rolling and rotating around a fixed leg, rigidity and tremor. These movement disorders correlated with the development of a spongiform encephalopathy, with the motor ganglia being preferentially affected (89). These observations demonstrate that mitochondrially generated ROS are acutely toxic to tissues and organs, apparently acting by inactivating iron-sulfur center containing enzymes of the tricarboxylic acid cycle and the ETC. In this regard, the MnSOD -/- mouse and the Friedreich ataxia patient have a similar pathophysiology. Hence, both mitochondrial ATP depletion and ROS generation are important in the pathophysiology of mitochondrial disease and hence potential factors in aging.

Fig. 2.1.
Fig. 2.1. Hypotheses for the mitochondrial basis of aging and degenerative diseases (1).

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