Influence of Macromolecules on the Permeability of Porin Pores and Dynamic Compartmentation of Adenine Nucleotides in the Mitochondrial Intermembrane Space
In the past, the biological relevance of mitochondrially localized ATP splitting enzymes such as hexokinase or creatine kinase has been discussed as an advantage in supplying these enzymes with mitochondrially formed ATP (Saks et al., 1974; Gellerich et al., 1977; Bessman & Gots, 1975). A new approach to this problem became possible through experiments with reconstituted systems (Gosalvez et al., 1974; Gellerich & Saks, 1982; Gellerich et al., 1987; Kottke et al., 1991), in which mitochondria and muscle pyruvate kinase compete for ADP produced by kinases in varied localization with respect to the mitochondrial outer membrane. For mitochondria from heart (Gellerich & Saks, 1982), liver (Gellerich, 1992), and brain (Kottke et al., 1991) it was shown that the ADP supply to oxidative phosphorylation was privileged via mitochondrial creatine kinase or adenylate kinase compared to the ADP supply by extramitochondrially added enzymes such as yeast hexokinase. Therefore, channelling of the extramitochondrially formed ADP into the mitochondria seems to be the crucial problem in cellular bioenergetics (Gellerich & Saks, 1982). In the resting muscle the cytosolic ADP is in the micromolar range whereas the concentrations of ATP, creatine phosphate and creatine are in the millimolar range (Wallimann et al., 1992). The low cytosolic ADP concentration is advantageous to the thermodynamic efficiency of the cell work but does not allow an optimal stimulation of oxidative phosphorylation. It is assumed that it is one of the main functions of the creatine phosphate shuttle to transport ADP into the mitochondria at low extramitochondrial ADP concentrations. In spite of extensive studies, the mechanism of the creatine phosphate shuttle is not yet completely understood. It was suggested that the compartmentalized creatine kinase isoenzymes may transport ADP by means of a metabolite shuttle (For a recent review see Wallimann et al., 1992). The general mechanism of metabolite shuttle is shown in the upper part of Fig. 1. In contrast to other well established metabolite shuttles such as the malate/aspartate shuttle which transport metabolites (hydrogen) through the mitochondrial inner membrane into the matrix space, metabolite shuttles into the mitochondrial intermembrane space are considered here. Therefore, these shuttles do not require translocator proteins, since their metabolites can diffuse through the porin pores. The metabolite A is reversibly transformed into the metabolite B. Both or only B diffuse into the intermembrane space, thus increasing the transport rate of A into the compartment. It is a prerequisite for a metabolite shuttle that the reaction A B has different directions in both compartments. In the lower part of Fig. 1, two shuttles are shown which are probably special forms of the general mechanism. One is the widely accepted creatine phosphate shuttle (Wallimann et al., 1992). As in the general scheme, the mitochondrial and the extramitochondrial creatine kinases act in different directions. Furthermore, this shuttle needs a sufficiently high creatine concentration since creatine instead of ADP (or both at elevated ADP concentrations) has to diffuse into the mitochondrial intermembrane space forming there ADP via mitochondrial creatine kinase. As a second ADP shuttle we propose the adenylate kinase shuttle acting in a way similar to that of the creatine phosphate shuttle. It may operate in tissues with sufficiently high adenylate kinase activities such as liver, some types of spermatozoa or muscles. This could be possible, since mitochondrial and cytosolic adenylate kinase isoenzymes are compartmentalized in a way similar to that of the creatine kinase isoenzymes. In this shuttle, AMP carries ADP equivalents (just as creatine) into the mitochondria: AMP formed in the cytosol from ADP via cytosolic adenylate kinase diffuses into the intermembrane space forming there ADP via mitochondrial adenylate kinase, and this ADP stimulates the oxidative phosphorylation.
KeywordsCreatine Kinase Pyruvate Kinase Mitochondrial Outer Membrane Adenine Nucleotide Adenylate Kinase
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