1 Mariannick Marcil, Karine Bourduas, Alexis Ascah, Yan Burelle ...

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DISCUSSION Results from the present study provide evidence that in heart mitochondria, the sensitivity to Ca 2+ -induced PTP opening is influenced by the type of respiratory substrate oxidized, with complex I donors acting as sensitizers compared to complex II substrates. In addition, the present results indicate that regular exercise training can decrease the sensitivity to Ca 2+ - induced PTP opening when mitochondria are energized with complex II substrates. This effect of training was observed in the absence of changes in the physiological modulators of PTP opening investigated. Substrate specific regulation of the PTP: Fontaine et al. (22) have shown that in skeletal muscle mitochondria CRC is 3-4 fold lower in mitochondria energized with glutamate-malate compared to succinate. This marked difference in CRC was shown to be due to the fact that the factors contributing to PTP opening are different in the two experimental conditions. Indeed, in presence of complex I substrates the electron flow through this complex, independent of other regulators (i.e. redox state of PN’s, , pH, ROS production), appeared to be the main factor regulating PTP opening by acting as a potent sensitizer (6, 22, 40). In contrast, when complex I was bypassed using succinate the mechanism was largely inactive and the contribution of other regulators to PTP opening were unmasked. Results from the present study are in line with these data. Indeed, in both experimental groups a substantially lower CRC was observed in presence of glutamate-malate compared to succinate. Our data thus indicate that similar to what is observed in skeletal muscle the electron flow through complex I sensitize heart mitochondria to PTP opening. Training-induced alteration in Ca 2+ handling: To our knowledge, the impact of exercise training on Ca 2+ handling by heart mitochondria has only been investigated in two studies (50, 56) and the effect on the PTP was not directly 14
assessed. Sordahl et al. (56) reported that the rate of Ca 2+ uptake by isolated heart mitochondria energized with succinate was unchanged following training in dogs. Similar finding were reported by Penpargkul et al. (50) in rodents in response to swim training. Results from the present study are in line with these findings. Indeed, Ca 2+ uptake kinetics measured during the first 2-3 Ca 2+ pulses of the Ca 2+ challenge did not differ between the two experimental groups whether mitochondria were energized with complex I or II substrates. These data thus suggest that training has little effect on the electrophoretic mechanism of Ca 2+ uptake in heart mitochondria. In the study by Sordahl et al. (56) training was found to decrease the capacity of mitochondria to accumulate Ca 2+ when energized with succinate. At the time this study was published, the existence of the PTP and the inhibitory effect of cyclosporins on pore opening were unknown. However, given the experimental conditions used, this phenomenon was likely caused by a premature opening of the PTP in mitochondria from trained animals. As for the study by Penpargkul et al. (50) the experimental conditions used did not allow to observe a permeability transition. In contrast to the results from Sordhal et al. (56) data from the present study indicate that in mitochondria from T rats the amount of Ca 2+ required to trigger PTP opening was significantly 45 % higher in presence of succinate both in presence and absence of rotenone. In addition, CsA increased CRC in both experimental groups but did not abolish the effect of training. These results thus indicate that in our conditions, training was able to decrease the sensitivity to Ca 2+ - induced PTP opening in presence of complex II substrates. In addition, the fact that the effect of training was not abolished by CsA used at a concentration 3 fold in excess of that required to fully inhibit PTP opening (15, 17, 47) suggests that the effect of training is not related to a reduction in the expression of cyclophilin-D or its interaction with other PTP components (3, 4). 15
Page 1 and 2: Articles in PresS. Am J Physiol Hea
Page 3 and 4: INTRODUCTION Mitochondria play a pi
Page 5 and 6: METHODS Animal care All experiments
Page 7 and 8: asal respiration due to the presenc
Page 9 and 10: Mitochondrial Adenylate Content End
Page 11 and 12: increase in CRC which was not stati
Page 13: otenone. No significant differences
Page 17 and 18: production (12, 26) as well as an a
Page 19 and 20: REFERENCES 1. Argaud L, Gateau-Roes
Page 21 and 22: 38. Kowaltowski AJ, Vercesi AE, and
Page 23 and 24: AKNOWLEDGEMENTS This work was suppo
Page 25 and 26: Table 2: Effect of exercise on mito
Page 27 and 28: Glut/mal Rotenone Antimycin A Oligo
Page 29 and 30: Ca2+ retention capacity (nmol.mg -1
Page 31 and 32: Fluorescence (A.U.) Fluorescence (A
Page 33 and 34: FIGURE LEGENDS Figure 1: Overview o

1 Mariannick Marcil, Karine Bourduas, Alexis Ascah, Yan Burelle ...

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