Respiratory chain impairment

Eaton, S. Pourfarzam, M. Bartlett, K. The effect of respiratory chain impairment of beta-oxidation in rat heart mitochondria. Biochem. J. 319 633-640 1996. 

This complex consists of four subunits, all of which are encoded on nuclear DNA, synthesized on cytosolic ribosomes, and transported into mitochondria. The succinate dehydrogenase (SDH) component of the complex oxidizes succinate to fumarate with transfer of electrons via its prosthetic group, FAD, to ubiquinone. It is unique in that it participates both in the respiratory chain and in the tricarboxylic acid (TC A) cycle. Defects of complex II are rare and only about 10 cases have been reported to date. Clinical syndromes include myopathy, but the major presenting features are often encephalopathy, with seizures and psychomotor retardation. Succinate oxidation is severely impaired (Figure 11). 

Abnormalities of the respiratoiy chain. These are increasingly identified as the hallmark of mitochondrial diseases or mitochondrial encephalomyopathies [13]. They can be identified on the basis of polarographic studies showing differential impairment in the ability of isolated intact mitochondria to use different substrates. For example, defective respiration with NAD-dependent substrates, such as pyruvate and malate, but normal respiration with FAD-dependent substrates, such as succinate, suggests an isolated defect of complex I (Fig. 42-3). However, defective respiration with both types of substrates in the presence of normal cytochrome c oxidase activity, also termed complex IV, localizes the lesions to complex III (Fig. 42-3). Because frozen muscle is much more commonly available than fresh tissue, electron transport is usually measured through discrete portions of the respiratory chain. Thus, isolated defects of NADH-cytochrome c reductase, or NADH-coenzyme Q (CoQ) reductase suggest a problem within complex I, while a simultaneous defect of NADH and succinate-cytochrome c reductase activities points to a biochemical error in complex III (Fig. 42-3). Isolated defects of complex III can be confirmed by measuring reduced CoQ-cytochrome c reductase activity. 

L-selegiline alters the redox state of ubiquinone, suggesting that the flow of electrons is impaired in the respiratory chain. Furthermore, a decrease in ubiquinone levels has been observed, whereas ubiquinol (reduced ubiquinone) concentrations are increased in the striatum. Ubiquinol levels have been shown to augment as a result of impaired mitochondrial respiration. For example, ubiquinol concentrations were demonstrated to increase in tubular kidney cells exposed to complex IV inhibitors and in disease states with defects in respiratory chain components. These results are also consistent with the hypothesis that L-selegiline enhances 02 formation by altering the rate of electron transfer within the respiratory chain leading to increases in SOD activities in the mouse striatum. 

TJam-deficient mice (/ cell-specific Tfam knockout) MtDNA depletion, respiratory chain deficiency Mitochondrial diabetes, impaired stimulus-secretion coupling in f cells in young mice, loss of f cells in older mice S12... 

These findings are consistent with impaired fatty-acid oxidation reduced mitochondrial entry of long-chain acylcarnitine esters due to inhibition of the transport protein (carnitine palmityl transferase 1) and failure of the respiratory chain at complex II. Another previously reported abnormality of the respiratory chain in propofol-infusion syndrome is a reduction in cytochrome C oxidase activity, with reduced complex IV activity and a reduced cytochrome oxidase ratio of 0.004. Propofol can also impair the mitochondrial electron transport system in isolated heart preparations. 

Mitochondrial dysfunction has long been considered to play a central role in the development of cell injury during ischemia-reperfusion and hypoxia-reoxygenation [19]. Besides the inhibition of fatty acid oxidation, mitochondrial energy generation is diminished because of defects in respiratory chain function. Inhi-hition of the FO-Fl-ATPase leading to impaired function of respiratory complex I has been observed in I/R injury. Similar to ischemia, dsplatin has been shown to affed mitochondrial respiratory complexes and func-... 

Impaired respiration also blocks the transfer of electrons along the respiratory chain, causing reduction of upstream respiratory chain components, which then react with oxygen to form the superoxide anion radical (Fig. 6). Increased ROS formation can damage mtDNA and respiratory polypeptides thus further impairing respiration. ROS may also play a role in necroinflammation and fibrosis (Pessayre and Fromenty 2005). 

Finally, severe impairment of respiration impairs mitochondrial 6-oxidation (Watmough et al. 1990). Normally the NADH formed by 6-oxidation is then reoxidized by the mitochondrial respiratory chain regenerating the NAD" required for fatty acid 6-oxidation. During severe impairment of respiration, NAD" regeneration cannot sustain 6-oxidation (Watmough et al. 1990), which impairs 6-oxidation... 

Fig. 6 Consequences of a primary impairment of mitochondrial respiration. The biock in the flow of electrons in the respiratory chain decreases ATP formation, thus causing ceii dysfimction or ceii death. It also causes the accumulation of electrons in upstream respiratory chain complexes, thus increasing ROS formation, which can cause oxidative stress and aging of mitochondrial DNA (mtDNA). Finally, the block in electron flow also decreases the reoxidation of NADH into NAD. A first consequence of the lack of NAD" is to decrease the 3-oxidation of fatty acids, thus causing steatosis. A second consequence is to decrease the oxidation of pyruvate by the pyruvate dehydrogenase complex. Pyruvate is not degraded and, due to the high NADH/NAD ratio, pyruvate is instead reduced into lactate, which can trigger lactic acidosis...

Thymidine triphosphate (TTP) depletion. AZT and thymidine (T) compete with each other for phosphorylation by thymidine kinase into AZT-monophosphate (AZT-MP) and thymidine-monophosphate (TMP), respectively (Fig. 13) (Lynx and McKee 2006). AZT can therefore decrease the formation of TMP and TTP, whose relative deficiency can then slow mtDNA replication (Lynx and McKee 2006). Interestingly the administratimi of uridine in animals and perhaps also in humans can prevent AZT, ddC, and d4T toxicity (Walker and Venhoff 2005 Banasch et al. 2006). Uridine administration may provide an alternate route for TTP synthesis, thus preventing TTP depletimi and the impairment of mtDNA replication (Lynx and McKee 2006). Furthermore, the uridine-induced restoration of mtDNA levels and respiratory chain functirm could improve the activity of dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in pyrimidine synthesis. Thus, a virtuous circle is initiated by uridine supplementation (Setzer et al. 2008). 

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