科研之友
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摘要
A number of findings in the 1950s had offered indirect indications that mitochondria could accumulate Ca(2+). In 1961, the phenomenon was directly demonstrated using isolated mitochondria: the uptake process was driven by respiratory chain activity or by the hydrolysis of added ATP. It could be accompanied by the simultaneous uptake of inorganic phosphate, in which case precipitates of hydroxyapatite were formed in the matrix, buffering its free Ca(2+) concentration. The properties of the uptake process were established in the 1960s and 1970s: the uptake of Ca(2+) occurred electrophoretically on a carrier that has not yet been molecularly identified, and was released from mitochondria via a Na(+)/Ca(2+) antiporter. A H(+)/Ca(2+) release exchanger was also found to operate in some mitochondrial types. The permeability transition pore was later also found to mediate the efflux of Ca(2+) from mitochondria. In the mitochondrial matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated in the matrix by the cycling of Ca(2+) across the inner membrane. In conditions of cytoplasmic Ca(2+) overload mitochondria could store for a time large amounts of precipitated Ca(2+)-phosphate, thus permitting cells to survive situations of Ca(2+) emergency. The uptake process was found to have very low affinity for Ca(2+): since the bulk concentration of Ca(2+) in the cytoplasm is in the low to mid-nM range, it became increasingly difficult to postulate a role of mitochondria in the regulation of cytoplsmic Ca(2+). A number of findings had nevertheless shown that energy linked Ca(2+) transport occurred efficiently in mitochondria of various tissues in situ. The paradox was only solved in the 1990s, when it was found that the concentration of Ca(2+) in the cytoplasm is not uniform: perimitochondrial micropools are created by the agonist-promoted discharge of Ca(2+) from vicinal stores in which the concentration of Ca(2+) is high enough to activate the low affinity mitochondrial uniporter. Mitochondria thus regained center stage as important regulators of cytoplasmic Ca(2+) (not only of their own internal Ca(2+)). Their Ca(2+) uptake systems was found to react very rapidly to cytoplasmic Ca(2+) demands, even in the 150-200 msec time scale of processes like the contraction and relaxation of heart. An important recent development in the area of mitochondrial Ca(2+) transport is its involvement in the disease process. Ca(2+) signaling defects are now gaining increasing importance in the pathogenesis of diseases, e.g., neurodegenerative diseases. Since mitochondria have now regained a central role in the regulation of cytoplasmic Ca(2+), dysfunctions of their Ca(2+) controlling systems have expectedly been found to be involved in the pathogenesis of numerous disease processes.
- 出版日期2010-7
