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

Martha E Gadd,Kimberly M Broekemeier,Elliott D Crouser,Jitendra Kumar,Gustav Graff,Douglas R Pfeiffer

doi:10.1074/jbc.m510845200

Martha E Gadd, Kimberly M Broekemeier + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m510845200

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Abstract

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.

Highlights

Mitochondria from rat liver and rabbit heart have been shown to contain a Ca2ϩ-independent phospholipase A23 that has a molecular mass of ϳ80 kDa [1, 2]
This study shows that on a longer time frame of hours, mitochondrial independent phospholipase A2 (iPLA2) activity does change the relationships between swelling and the release of an apoptogenic factor, both in terms of the time course involved and the fraction released at a given extent of swelling
IPLA2 Activity Produces the free fatty acids (FFA) Accumulation That Accompanies Ca2ϩ Uptake—It has long been known that energy-dependent Ca2ϩ accumulation provokes a limited hydrolysis of phospholipids and an accumulation of FFA [18]

Summary

Introduction

Mitochondria from rat liver and rabbit heart have been shown to contain a Ca2ϩ-independent phospholipase A2 (iPLA2) that has a molecular mass of ϳ80 kDa [1, 2]. 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 iPLA2 in vivo, with a resulting accumulation of free fatty acids in mitochondria. This study shows that on a longer time frame of hours, mitochondrial iPLA2 activity does change the relationships between swelling and the release of an apoptogenic factor (cytochrome c), both in terms of the time course involved and the fraction released at a given extent of swelling Aspects of these findings have been described in abstract form [14]

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