Effect of buffers and osmolality on anion uniport across the mitochondrial inner membrane

Ng, Lay Tin; Selwyn, Michael J.; Choo, Hui Lim

doi:10.1016/0005-2728(93)90212-x

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…Consistent with the mechanism shown in Fig. 7 and reports describing the solute selectivity of IMAC (26), swelling seen during the first 2-3 h of incubation was reduced upon substituting the deprotonated form of MES for Cl Ϫ in the medium, to the point that no disruption of mitochondrial membranes occurred during this period, and there was no release of cytochrome c. The presence of BEL extended the period of minimal swelling and the retention of membrane integrity to about 4 h. During the period between 4 and 8 h, significant swelling and membrane disruption did occur, but the final extent was diminished compared with that seen in the absence of BEL. The questions then arising are how iPLA 2 activity promotes the release of cytochrome c and whether this action might be important in the process of apoptosis.…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, since the matrix space K ϩ concentration is similar to that of the external medium, it appeared that the Cl Ϫ concentration gradient was the one of greatest interest. A scheme involving the mitochondrial inner membrane anion channel (IMAC) and the K ϩ /H ϩ antiporter can account for the swelling, as further described under "Discussion," which led us to substitute zwitterions for Cl Ϫ (poor substrates for IMAC (26,27)) as a way to diminish the initial swelling seen in Fig. 4.…”

Section: Figure 2 Relationships Between Camentioning

confidence: 99%

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Mitochondrial iPLA2 Activity Modulates the Release of Cytochrome c from Mitochondria and Influences the Permeability Transition

Gadd

Broekemeier

Crouser

et al. 2006

Journal of Biological Chemistry

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The mitochondrial Ca 2؉ -independent phospholipase A 2 is activated during energy-dependent Ca 2؉ accumulation under conditions where there is a sustained depression of the membrane potential. This activation is not dependent on induction of the mitochondrial permeability transition. Bromoenol lactone, which inhibits the phospholipase, is effective as an inhibitor of the transition, and this action can be overcome by low levels of exogenous free fatty acids. Apparently, activation of the Ca 2؉ -independent phospholipase is a factor in the mechanisms by which depolarization and Ca 2؉ accumulation promote opening of the permeability transition pore. Sustained activity of the Ca 2؉ -independent phospholipase A 2 promotes rupture of the outer mitochondrial membrane and spontaneous release of cytochrome c on a time scale similar to that of apoptosis occurring in cells. However, more swelling of the matrix space must occur to provoke release of a given cytochrome c fraction when the enzyme is active, compared with when it is inhibited. Through its effects on the permeability transition and release of intermembrane space proteins, the mitochondrial Ca 2؉ -independent phospholipase A 2 may be an important factor governing cell death caused by necrosis or apoptosis.Mitochondria from rat liver and rabbit heart have been shown to contain a Ca 2ϩ -independent phospholipase A 2 (iPLA 2 ) 3 that has a molecular mass of ϳ80 kDa (1, 2). Like phospholipases of this type from other sources (3, 4), the mitochondrial enzyme is inactivated by bromoenol lactone (BEL), which acts through an activity-dependent mechanism, leading to a covalent modification within the active site (5). No physiological function of the iPLA 2 in mitochondria has been established, but it has been shown that pretreatment with BEL attenuates the loss of phospholipids that accompanies ischemia/reperfusion injury and reduces the size of infarcts by ϳ50% (2).The relationship between mitochondrial energetic status and iPLA 2 activity is an important factor to consider when contemplating potential physiological and pathophysiological roles of the enzyme. More specifically, activity is not seen in mitochondria that are respiring under state 4 conditions but is manifest upon the addition of uncoupler and is fully manifest following the development of inner membrane pores (1). The former property suggests that transient periods of deenergization might cause a transient activation of the iPLA 2 in vivo, with a resulting accumulation of free fatty acids in mitochondria. Such an accumulation could be of interest in many regards, including opening of the permeability transition pore, which is favored by low levels of these compounds (6 -8). Occurrence of the permeability transition leads to apoptosis in many cell types (9 -11), so scenarios arise in which the iPLA 2 contributes to the control of apoptosis by influencing the permeability transition and wherein the facilitative effects of depolarization on the transition (12, 13) might occur through activity of this enzyme...

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Section: Discussionsupporting

confidence: 91%

Section: Figure 2 Relationships Between Camentioning

confidence: 99%

Mitochondrial iPLA2 Activity Modulates the Release of Cytochrome c from Mitochondria and Influences the Permeability Transition

Gadd

Broekemeier

Crouser

et al. 2006

Journal of Biological Chemistry

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The mitochondrial inner membrane anion channel is inhibited by DIDS

Beavis

Davatol-Hag

1996

J Bioenerg Biomembr

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The mitochondrial inner membrane anion channel (IMAC) is a channel, identified by flux studies in intact mitochondria, which has a broad anion selectivity and is maintained closed or inactive by matrix Mg2+ and H+. We now present evidence that this channel, like many other chloride/anion channels, is reversibly blocked/inhibited by stilbene-2,2'-disulfonates. Inhibition of malonate transport approaches 100% with IC50 values of 26, 44, and 88 mu M for DIDS, H2-DIDS, and SITS respectively and Hill coefficients < or = 1. In contrast, inhibition of Cl- transport is incomplete, reaching a maximum of about 30% at pH 7.4 and 65% at pH 8.4 with an IC50 which is severalfold higher than that for malonate. The IC50 for malonate transport is decreased about 50% by pretreatment of the mitochondria with N-ethylmaleimide. Raising the assay pH from 7.4 to 8.4 increases the IC50 by about 50%, but under conditions where only the matrix pH is made alkaline the IC50 is decreased slightly. These properties and competition studies suggest that DIDS inhibits by binding to the same site as Cibacron blue 3GA. In contrast, DIDS does not appear to compete with the fluorescein derivative Erythrosin B for inhibition. These findings not only provide further evidence that IMAC may be more closely related to other "Cl-" channels than previously thought, but also suggest that other Cl- channels may be sensitive to some of the many regulators of IMAC which have been identified.

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Effect of buffers and osmolality on anion uniport across the mitochondrial inner membrane

Cited by 2 publications

References 40 publications

Mitochondrial iPLA2 Activity Modulates the Release of Cytochrome c from Mitochondria and Influences the Permeability Transition

Mitochondrial iPLA2 Activity Modulates the Release of Cytochrome c from Mitochondria and Influences the Permeability Transition

The mitochondrial inner membrane anion channel is inhibited by DIDS

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