Diversity of Mitochondrial among Organs Evidence from Metabolic Pathways

It has been well-known that some organ-specific metabolic pathways represent good examples of mitochondrial diversity (33).

3.1. Liver mitochondria

Synthesis of carbamoyl-phosphate and citrulline, first two steps of urea synthesis, is located only within liver mitochondria. A liver-specific ornithine-citrulline antiporter is responsible for the import of ornithine into, and the export of citrulline out of the liver mitochondria (33). Gluconeogenesis is a liver- and kidney-specific pathway. The formation of oxaloacetate occurs via pyruvate carboxylase in the mitochondrial matrix and plays a central role in controlling gluconeogenesis (24). Another peculiarity of liver mitochondria is the generation of the ketone bodies acetoactate and b-hydroxybutyrate from acetyl-CoA. b-hydroxy-butyrate dehydrogenase, which converts acetoacetate to b-hydroxy-butyrate using mitochondrial NADH, is liver-specific mitochondrial enzyme and can therefore be used to indicate mitochondrial NAD-redox state in liver (54).

Figure 1. Different respiration rates and activities of ETC complex I and IV in muscle versus brain mitochondria. The inhibition plots are constructed from the relative ADP-stimulated 02 consumption rates plotted against the percentage decrease in NADHxoenzyme Q1 reductase activity (complex I) at identical concentrations of amytal (•) and rotenone (■) (A and B) or plotted against the percentage decrease in COX activity (complex IV) at identical KCN concentrations (C and D). The intersection of the regression line with the ordinate gives the reserve capacity of the enzyme investigated (From Ref. 33).

Figure 1. Different respiration rates and activities of ETC complex I and IV in muscle versus brain mitochondria. The inhibition plots are constructed from the relative ADP-stimulated 02 consumption rates plotted against the percentage decrease in NADHxoenzyme Q1 reductase activity (complex I) at identical concentrations of amytal (•) and rotenone (■) (A and B) or plotted against the percentage decrease in COX activity (complex IV) at identical KCN concentrations (C and D). The intersection of the regression line with the ordinate gives the reserve capacity of the enzyme investigated (From Ref. 33).

3.2. Kidney Mitochondria

Mitochondrial glutaminase I, catalyzes the kidney-specific desamination of glutamine to glutamate and ammonium ions (30).

3.3. Sperm Mitochondria

An intriguing property of sperm mitochondria is the existence of a lactic dehydrogenase, which is in redox equilibrium with the mitochondrial NADsystem (11, 39). This presumably allows a very effective utilization of lactic acid, which is present in high quantities in the fluids of the female genital tract.

This diversity of mitochondrial function among organs is not restricted only within specific metabolic pathways due to the presence or absence of a specific enzyme. The overall function of mitochondria, as measured by respiration (i.e., 02 consumption) from different organs is often different, suggesting differences in the expression or the activity of ETC complexes. In Figure 1, differences in the respiration between brain and muscle mitochondria are shown. The difference in the activities of complex I and IV (cytochrome c oxidase, COX) is shown by the response to complex I and IV inhibitors (rotenone and cyanide), while the experimental conditions are the same.

Differential expression of complex I has been described in the brain (43) and significant diversity has also been described in complex IV (COX) (33). Isoforms have been found for several COX subunits and are expressed in a tissue-specific and developmental manner (Fig. 2) (33). For example, for the isoform of subunit IV, high IV-2 expression was observed in adult lung and lower expression in all other tissues investigated, including fetal lung, implying that there may be effects of 02 on ETC subunit gene expression (26) (Fig. 2).

Figure 2. Diversity of cytochrome c oxidase isoforms mRN A expression in human and rat tissues. A: Northern blot analysis showing mRNA expression of cox-IV-1 and cox-IV-2 in human fetal (f) and adult tissues. The developmental stage of fetal tissues is 20 (brain), 24 (liver), 37 (lung), and 28 (muscle) weeks. B: Quantitative PCR analysis of mRNA levels of the cytochrome c oxidase subunit IV-2 isoform in rat tissues (From Ref. 26).

Figure 2. Diversity of cytochrome c oxidase isoforms mRN A expression in human and rat tissues. A: Northern blot analysis showing mRNA expression of cox-IV-1 and cox-IV-2 in human fetal (f) and adult tissues. The developmental stage of fetal tissues is 20 (brain), 24 (liver), 37 (lung), and 28 (muscle) weeks. B: Quantitative PCR analysis of mRNA levels of the cytochrome c oxidase subunit IV-2 isoform in rat tissues (From Ref. 26).

Diversity in the expression of the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) isoforms has also been described (10). PDK-2 is differentially expressed in the lungs versus the heart or systemic smooth muscle. Thus the PDK-2 inhibitor dichloroacetate (lower K^ for PDK-2 than for PDK 1 -3-4) (10) may have selective effects on the pulmonary circulation. This is in agreement with the finding that dichloroacetate reverses pulmonary hypertension (perhaps via redox effects on K+ channel expression and function) without affecting the left ventricle or lowering systemic blood pressure (38). This is an example of taking advantage of mitochondrial diversity to design therapeutic strategies for vascular disease that are selective and specific.

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