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Increases ATP production Ca 2+ homeostasis Fatigue/disease/apoptosis/cell death Protein synthesis

Mitochondria and Ca 2+ Why bother?. Increases ATP production Ca 2+ homeostasis Fatigue/disease/apoptosis/cell death Protein synthesis Signals to new sites e.g. RYR, IP 3. Rizzuto et al., Oncogene (2003) 22, 8619-8627. Maternally transmitted Polarised -150 – 200 mV

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Increases ATP production Ca 2+ homeostasis Fatigue/disease/apoptosis/cell death Protein synthesis

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  1. Mitochondria and Ca2+ Why bother? • Increases ATP production • Ca2+ homeostasis • Fatigue/disease/apoptosis/cell death • Protein synthesis • Signals to new sites e.g. RYR, IP3

  2. Rizzuto et al., Oncogene (2003) 22, 8619-8627.

  3. Maternally transmitted Polarised -150 – 200 mV More cristae = more ATP Epithelial cells, few Muscle, up to 1000 per cell

  4. How to tackle mitochondria? • Since 1961, isolate them from tissue alter function, lose regulatory factors • Since early 1990’s, study them in situ • O2 consumption, intrinsic fluorescence, • Use fluorescent dyes (Ca2+, ROS, Memb. pot.)

  5. Mitochondrial Ca2+ entry and release CGP-37157

  6. Blocking Ca2+ entry and exit • Depolarise mitochondria: FCCP • Inhibit Ca2+ uniporter: Ru360 • Na+-Ca2+ exchanger: CGP37157 • H+-Ca2+ exchanger ? • MTP: Cyclosporin A ??

  7. Mitochondria selectively take up Ca2+ but no other physiologically relevant ion. , Na+, K+ Kirichok et al., Nature (2004) 427, 360-4.

  8. Mitochondrial mysteries • Structures of all Ca2+ transport related proteins are unknown. • Structure of mitochondrial transition pore (MTP, PTP, MPTP) also unknown. • Mitochondrial myopathies.

  9. Mouse muscle • 10–15% fibre volume • Denser at surface • Fixed positions with • desmin + plectin • Close to Ca2+ release site

  10. In mammalian muscle, mitochondria are near transverse tubules

  11. Csordás et al., Trends Cardiovasc Med. 2001 11 269-275

  12. General model of Ca2+ stimulation of ROS production

  13. Measure mitochondrial Ca2+ and ROS simultaneously

  14. In motor neurones, mitochondria limit increase in cytosolic Ca2+ Mitochondria Cytosol David et al. J Physiol 1998 509, 59-65

  15. Useful links for confocal users • http://rsb.info.nih.gov/ij • http://www.tsienlab.ucsd.edu/ • http://www.invitrogen.com/site/us/en/home/support/Tutorials.html

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