Mitochondria calcium

The second phase of the process involves a massive increase in intracellular calcium concentrations. Interestingly, the calcium entry through NMDA receptors is particularly toxic, with one immediate pathogenic target of calcium entry being the mitochondrion [19]. 

As the power house of the cell, the mitochondrion is essential for energy metabolism. As the motor of cell death (1), this organelle is central to the initiation and regulation of apoptosis. In addition, mitochondria are critically involved in the modulation of intracellular calcium concentration and the mitochondrial respiratory chain is the major source of damaging reactive oxygen species. Mitochondria also play a crucial role in numerous catabolic and anabolic cellular pathways. 

It has been known for many years that the mitochondrion shows a respiration-linked transport of a number of ions. Of these, calcium has attracted the most attention since it depends on a specific transport system with high-affinity binding sites. The uptake of calcium usually also involves a permeant anion, but in the absence of this, protons are ejected as the electron transfer system operates. The result is either the accumulation of calcium salts in the mitochondrial matrix or an alkalinization of the interior of the mitochondrion. The transfer of calcium inwards stimulates oxygen utilization but provides an alternative to the oxidative phosphorylation of ADP618 ... 

The transport of calcium into the mitochondrion can lower external Ca2+ to levels of 1 to 0.1 jumole/1. This has, therefore, been interpreted as a basic mechanism in maintaining intracellular calcium at these levels. Only about 3 % of the calcium which passively diffuses into the cell is expelled by a calcium pump into the plasma membrane, whereas the remaining 97 % is sequestered into the mitochondria. This occurs because both processes have similar rate constants, but the total mitochondrial surface is some 30 times larger than that of the plasma membrane. This argument presupposes, however, that the calcium which enters the cell is equally available to both sets of membranes. 

The mechanism by which the mineral leaves the mitochondrion is only one of the problems of this theory. The mineral in the mitochondrion exists in association with the fluid contents. Thus, unless this water is in some structural form with abnormal solubilities, the mineral must be saturating the fluid, and solubility products apply. It follows that the mitochondrial calcium and phosphate concentrations must be similar to those of the extracellular fluids, i. e. calcium must be concentrated thousandfold to overcome the low intracellular values. 

Calcium levels are believed to be controlled in part at least by the uptake and release of Ca2+ from mitochondria.172"174 The capacity of mitochondria for Ca2+ seems to be more than sufficient to allow the buffering of Ca2+ at low cytosol levels. Mitochondria take up Ca2+ by an energy-dependent process either by respiration or ATP hydrolysis. It is now agreed that Ca2+ enters in response to the negative-inside membrane potential developed across the inner membrane of the mitochondrion during respiration. The uptake of Ca2+ is compensated for by extrusion of two H+ from the matrix, and is mediated by a transport protein. Previous suggestions for a Ca2+-phosphate symport are now discounted. The possible alkalization of the mitochondrial matrix is normally prevented by the influx of H+ coupled to the influx of phosphate on the H - PCV symporter (Figure 10). This explains why uptake of Ca2+ is stimulated by phosphate. Other cations can also be taken up by the same mechanism. 

Fig. 17.6. The vectorial pumping of calcium ions and protons across the mitochondrion membranes. A schematic enlargement of the inner (cristae) membrane is shown to indicate the existence of protein-based electron (e ) and proton (H+) conduction pathways (from Ref. 26 with permission).

A FIGURE 5-26 Electron micrograph of a mitochondrion. Most ATP production in nonphotosynthetic cells takes place in mitochondria. The inner membrane, which surrounds the matrix space, has many infoldings, called cristae. Small calcium-containing matrix granules also are evident. [From D. W. Fawcett, 1981, The Cell, 2d ed., Saunders, p. 421.]... 

The energy for Ca uptake can be derived either from substrate oxidation or from ATP hydrolysis. Since adenine nucleotides stabilise calcium phosphate precipitates the presence of adenine nucleotides stimulates Ca uptake, even if it is respiration-driven [125]. It is generally found that 2 Ca ions enter the mitochondrion at the expense of 1 ATP or its equivalent [124]. It is, however, less clear how many electrical charges cross the membrane during this process. Most experiments indicate that free Ca, carrying 2 positive charges, is the mobile species [126,127]. Some experiments suggest, however, that a complex of the form (CaX), in which X is a monovalent anion (for instance phosphate), moves [128]. The distinction between these two possibilities plays an important role in the discussion on the stoichiometry of the mitochondrial H pump. 

Considerable evidence now supports the hypothesis that the inner membrane of a rat liver mitochondrion contains a specific permease or carrier for Ca, which makes possible the inward transport of this cation from regions of low concentration in response to electrochemical gradients generated by electron transport. The carrier has a very hig affinity for Ca + and it also has the ability to transport Sr + and Mn + but not Mg +. Lehninger has discussed mitochondrial transport of calcium he has also shown " that La + is a specific inhibitor of the Ca + carrier and is therefore a potential probe for calcium transport. The dye Ruthenium Red also inhibits calcium transport and, since this dye reacts specifically with mucopolysaccharides, it has been concluded that the latter (in the form of mucoproteins or muco- or glyco-lipids) are at the active centre of the sites of mediation of mitochondrial Ca + transport. Fluorescence enhancement of 8-anilino-l-naphthalene has also been used as a probe for calcium transport. 

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