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LETTERS |
Refering to the studies by Dorsten et al. (1997), Pucar et al. (2001) and Janssen et al. (2003), the authors argued that elevated energy demand would strengthen rather than decrease the functional coupling between miCK and oxidative phosphorylation. Saks et al. suggest that contracture of the fibres due to elevated free calcium concentration results in disturbance of cellular architecture, changes the diffusion restriction for ADP, which in turn explains the decrease of the apparent Km for exogenous ADP, and thereby that this phenomenon is not related to a direct effect of calcium itself.
In fact, we do not reject this assumption (see Discussion and Conclusion sections), and we do not think either that the increase in mitochondrial affinity for ADP results from a direct calcium effect. Indeed, as underlined in the paper, the loss of calcium effect upon respiration in the presence of an inhibitor of myosin-ATPase activity emphazises a role for this enzyme (and not directly calcium) in the modification of mitochondrial respiration. Therefore, based on previous studies demonstrating the existence of a direct ADP channelling between mitochondria and myosin-ATPase, i.e. an apparent preference of mitochondria for endogenously produced ADP (Kummel, 1988; Seppet et al. 2001), we also proposed a second hypothesis: calcium, by increasing myosin-ATPase activity, could increase the rate of endogenous ADP formation. This would in turn increase the feedback of ADP to the ANT, in the same manner as for the CK reaction. The recent study of Birkedal & Gesser (2004) using either exogenously added or endogenous (ATP addition) ADP further supports this hypothesis. Thus, we proposed that at least three energy transfer systems could coexist within the fibres, the CK- and AK-catalysed phosphotransfer and a direct transfer of adenine nucleotides between mitochondria and myosin-ATPases. In the part of the experiment related to the effect of Ca2+ and creatine, we do agree with the authors of this letter that muscle fibres did not relax because of continuously high free calcium levels (which thus differs from in vivo conditions). In these conditions, the enhancement of mitochondrial respiration, due to the marked increase in mitochondrial affinity for ADP, could have indeed reduced the possibility for any additional stimulation by creatine, although mitochondrial respiration in the presence of calcium represented roughly only 80% of the maximal respiration rate (and not 100% as assumed by Saks et al.). However, this doesn't mean (and we did not want to let it be thought), that the miCK system is really no longer functionally coupled with mitochondrial respiration in vivo. This does not, either, counteract the possibility of the existence of an alternative (additional) mechanism allowing an effective transfer of ADP from myosin-ATPases towards mitochondria (Birkedal & Gesser, 2004).
Rather, we suggest in our discussion that the relative importance of each phosphotransfer system would depend on fibre activity, and that calcium-induced myosin-ATPases activation could progressively increase the contribution of direct ADP channeling to total cellular phosphotransfer at the expense of the CK-mediated one. Indeed, previous studies have already demonstrated (i) a decreased contribution of CK-phosphotransfer to total ATP flux in response to muscle workload (while the contribution of AK-catalysed transfer increased) (Janssen et al. 2003), and (ii) an interrelation between diverse phosphotransfer pathways depending on cellular activity (Dzeja & Terzic, 2003). Furthermore, the existence of a third phosphotransfer pathway, i.e. a direct channelling of adenine nucleotide during strong elevation of energy needs, would explain the discrepancy between some in vivo studies indicating either an increased CK flux during work output (Dorsten et al. 1997; Janssen et al. 2003; cited by Saks et al.), or no change of CK-catalysed phosphotransfer during strong increases in cellular ATPase activities (Brindle et al. 1989; McFarland et al. 1994).
In conclusion, at this stage, we are far from drawing definitive conclusions, and we think that understanding the actual mechanisms involved in the modification of mitochondrial respiration regulation following calcium-induced activation of myosin-ATPase (and/or contraction) clearly needs further investigation. Indeed, metabolic compartments and cell architecture, but also cell activity, must be taken into account when studying metabolic regulation. For this, a sophisticated approach needs to be used but, to our knowledge, no model is available to simultaneously measure mitochondrial respiration, phosphotransfer pathways (AK-, CK-catalysed phosphotransfer and possible direct ADP channelling) and muscle fibre contraction.
UMR SENAH, INRA, 35590, Saint-Gilles France Email: naiggueguen{at}yahoo.fr
References
Birkedal R & Gesser H (2004). J Comp Physiol [B] 174, 255–262.[CrossRef][Medline]
Brindle KM et al. (1989). Biochemistry 28, 4887–4893.[CrossRef][Medline]
Dorsten FA et al. (1997). Biochem J 325, 411–416.[Medline]
Dzeja P & Terzic A (2003). J Exp Biol 203, 2039–2047.
Gueguen N et al. (2005). J Physiol 564, 723–735.
Janssen E et al. (2003). J Biol Chem 278, 30441–30449.
Kummel L (1988). Cardiovasc Res 22, 359–367.[Medline]
McFarland EW et al. (1994). Biophys J 67, 1912–1924.
Pucar D et al. (2001). J Biol Chem 276, 44812–44819.
Seppet EK et al. (2001). Biochim Biophys Acta 1504, 379–395.[Medline]
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