Abstract
Isolated rat liver mitochondria undergo swelling in the presence of certain substances of physiological occurrence which include inorganic phosphate (I), Ca*, (2), L-thyroxine (2, 3), reduced glutathione (4)) and an isooctane-soluble uncoupling agent formed enzymatically in mitochondria, designated U factor (5). Such swelling, with the exception of that brought about by glutathione (4), has been found to be reversed by the addition of adenosine triphosphate + Mg* + serum albumin, with extrusion of water from the mitochondria (6, 7). Adenosine triphosphate also reverses swelling produced by such nonphysiological agents as arsenate (7) and phlorizin (7, 8). These and other aspects of mitochondrial swelling and contraction1 have been reviewed in detail by Lehninger (9, 10). The failure of ATP to reverse mitochondrial swelling induced by glutathione appeared to be a significant exception, since swelling of this type is more drastic and apparently diierent in kind from that produced by the other agents listed (4, 11). In this paper it is shown that although ATP will not contract glutathione-swollen mitochondria in relatively dilute suspensions as are ordinarily used in such assays, it will produce contraction when relatively dense suspensions of mitochondria are employed. The dependence of the ATPlinked contraction on the concentration of mitochondria led to the finding that exposure of mitochondria to GSH causes leakage into the medium and dilution of a critical heat-labile factor. This substance, designated “contraction factor,” or C factor, is apparently a protein and is shown to be required, together with ATP, Mg*, and bovine serum albumin, for the reversal of glutathione-induced swelling. Leakage of C factor reduces its effective concentration below a critical level in dilute suspensions of mitochondria swollen with GSH. A preliminary account of these and some related findings has been published (12) and the following papers describe further investigations on this subject (13).2* 3
Highlights
Prepa-The dependenceof the ATPlinked contraction on the concen- rations of GSH provided by Boehringerund Sijhne,Ingelheim, tration of mitochondria led to the finding that exposure of West Germany, containing lessthan 2% GSSG erefound satisfactory; tion of a critical heat-labile factor
The experiments described in this paper show that glutathione causes release of a heat-labile factor, apparently of a specific nature, which is necessary in the adenosine triphosphate (ATP)-induced contraction of glutathione-swollen mitochondria
Rat liver mitochondria in suspensions of relatively low density swell rapidly in the presence of reduced glutathione but do not contract again on addition of adenosine triphosphate (ATP) ; this behavior is anomalous since swelling under the same conditions induced by other agents such as phosphate, thyroxine, Ca*, and phlorizin, is rapidly reversed by ATP
Summary
The dependenceof the ATPlinked contraction on the concen- rations of GSH provided by Boehringerund Sijhne,Ingelheim, tration of mitochondria led to the finding that exposure of West Germany, containing lessthan 2% GSSG (measuredby mitochondriato GSH causesleakageinto the mediumand dilu- assaywith TPN-glutathione reductase4w) erefound satisfactory; tion of a critical heat-labile factor. A preliminary account of theseand somerelated findingshas of ATP + MgClz + bovine serumalbumin (SA) after swelling beenpublished [12] and the following papersdescribefurther failed to produce significant reversal [4, 7] The experiment investigationson this subject [13].2*3 summarizedin Fig. 1 shows that reversal of GSH-induced swellingof liver mitochondriaby ATP + Mg* + SA can, in EXPERIMENTAL
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