Mitochondria and glucose oxidation

1. Mitochondria and glucose oxidation • Mitochondrial structure and location • Pyruvate oxidation • Krebs cycle • Electron transport system • Creatine phosphate shuttle • Free radical production • Effects of training on mitochondria • Mitochondrial PO2 during exercise

2. Mitochondria Brooks et al.

3. Mitochondria Brooks et al.

4. Mitochondria Brooks et al.

5. Mitochondria Brooks et al.

6. Glycolysis • Shuttles for moving reducing equivalents from the sarcoplasm into the mitochondria: • Malate-aspartate shuttle • Glycerol phosphate shuttle • (Intracellular) Lactate shuttle • mMCT – mitochondrial monocarboxylate transporter Juel and Halestrap, J Physiol 517: 633, 2000

7. Mitochondria - PDH Pyruvate oxidation Primary functions: 1. Produce acetyl- CoA 2. Produce H+ (1 pair per pyruvate oxidized) Also, 1 CO2 is produced in the reaction(s) Murray et al., Harpers Biochemistry, Lange, 1996

8. Mitochondria – PDH Spriet and Heigenhauser, Exerc Sport Sci Rev 30: 91, 2002

9. Mitochondria –acetyl-CoA oxidation Krebs, or citric acid cycle Primary functions: 1. Produce H+ (4 pairs/cycle) 2. Produce ATP (GTP) at the “substrate level” (1/cycle) All of the CO2 from glucose metabolism is produced in the PDH reaction and Krebs cycle Brooks et al.

10. Mitochondria –acetyl-CoA oxidation Regulation of the Krebs cycle Primary mechanisms: 1. High NADH/NAD+ (low redox state) inhibits the dehydrogenases 2. NADH directly inhibits isocitrate dehydrogenase 3. Succinyl-CoA inhibits citrate synthase and α-ketoglutarate dehydrogenase Brooks et al.

11. Mitochondria – electron transport system Murray et al., Harpers Biochemistry, Lange, 1996

12. Mitochondria – electron transport system Chemiosmotic theory of oxidative phosphorylation Murray et al., Harpers Biochemistry, Lange, 1996

13. Mitochondria – electron transport system Murray et al., Harpers Biochemistry, Lange, 1996

14. Mitochondria – glucose oxidation Murray et al., Harpers Biochemistry, Lange, 1996

15. Mitochondria – creatine phosphate shuttle Function of the shuttle is to facilitate diffusion of high energy phosphate between mitochondria and the contractile apparatus Murray et al., Harpers Biochemistry, Lange, 1996

16. Mitochondria – free radical production Free radical: an atom or molecule with an unparied electron in the outer valence During mitochondrial respiration, O2 may lose an electron becoming a superoxide, O2−, which can react with other molecules (e.g., DNA, RNA, proteins, lipids) causing damage to the molecules The mitochondrial enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT), serve to neutralize the reactive species.

17. Mitochondria – free radical production GSH: reduced glutathione; GSSH: glutathione disulfide Powers and Shanely, Exerc Sport Sci Rev 30: 69, 2002

18. Mitochondria – effects of training Brooks et al.

19. Mitochondria – effects of training Brooks et al.

20. Mitochondria – effects of training Rate of Acetyl-CoA Oxidation The KM, or the “quality” of the enzymes doesn’t change, just the quantity [Acetyl-CoA] Brooks et al. (adapted from Fig. 7-11)

21. Mitochondria – effects of training Brooks et al.

22. Mitochondria – effects of training Although the exact molecular signal(s) involved in initiating mitochondrial biogenesis during training is not known, the increased Ca2+ is hypothesized. Brooks et al.

23. Mitochondria – PO2 during exercise Brooks et al.

24. Mitochondria – PO2 during exercise Brooks et al.