- The glycerol-3-phosphate and malate-aspartate shuttles both transport electrons into the mitochondria from cytoplasmic NADH. Explain how the glycerol-3-phosphate shuttle is more thermogenic than the malate-aspartate shuttle. Why are there two separate transport systems?
- Describe how increased synthesis of a UCP could decrease ATP synthesis.
- How many 360-degree rotations of ATP synthase occur as a result of one turn of the TCA cycle if all components are fully coupled?
- Which type of inhibitors would mimic a genetic defect in cytochrome oxidase?
- Describe how a deficiency in riboflavin could severely impair ATP synthesis.
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| The electron transport system consists of at least eight major electron carriers that are located in the inner mitochondrial membrane, each of which is isolable as a complex or as a single molecule. Electrons from four major flavoproteins feed electrons to ubiquinone, the first member of the common pathway. Energy derived from the conductance of electrons through the electron transport system is used by three of the complexes to pump protons into the intermembrane space, creating an electrochemical gradient or proton motive force. The proton gradient is used to power ATP synthase for
synthesis of ATP by rotary catalysis. Numerous toxins can severely impair the electron transport system, the ATP synthase and the translocase that exchanges ATP and ADP across the inner mitochondrial membrane. The rate of ATP production by the electron transport system is regulated by modulation of the proton gradient, by allosteric modification and phosphorylation-dephosphorylation and by thyroid hormones. At least five uncoupling proteins (UCP) with specific tissue distributions occur in the inner mitochondrial membrane, and they all regulate the membrane potential and thermogenesis. Chronic diseases or conditions, such as diabetes, cancer, obesity, and aging all have metabolic links to dysregulation of oxidative phosphorylation through effects on electron transport system and ATP synthase.
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| Argyropoulos G, Harper ME. Uncoupling proteins and thermoregulation. J Appl Physiol 2002;92(5):2187-98.
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Bender E and Kadenbach B. The allosteric ATP-inhibition of cytochrome c oxidase is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett 2000;466:130-134.
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| Højlund K, et al. Proteome analysis reveals Phosphorylation of ATP synthase subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J Biol Chem 2003;278(12):10436-10442.
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| Jezek P. Possible physiological roles of mitochondrial uncoupling proteins, UCPn. Int J Biochem Cell Biol 2002;34(10):1190-206.
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| Kadenbach B. Instrinsic and extrinsic uncoupling of phosphorylation. Biochim Biophys Acta -Bioenergetics 2003;1604(2):77-94.
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| Oldfors A, Tulinius M. Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 2003;62:217-227.
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| S. Papa, et al. Minireview. The NADH: ubiquinone oxidoreductase (complex I) of the mammalian respiratory chain and the cAMP cascade. J Bioenerg Biomembr 2002;34: 1-10.
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| Vidal-Puig, AJ. Uncoupling expectations. Nature Genet 2000;26(4):387-388.
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| Zhang, CY, et. al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, cell dysfunction, and type 2 diabetes. Cell 2001;105:745-755.
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