Kinetic evidence for a heart mitochondrial pore activated by Ca²⁺, inorganic phosphate and oxidative stress

Abstract

Evidence that the CaZ +-induced permeabilization of mitochondria is attributable to a reversible Ca2+-activated pore [A1 Nasser & Crompton (1986) Biochem. J. 239,[19][20][21][22][23][24][25][26][27][28][29] CoA, Mg2 ', AMP and also ATP, when account is taken of ADP arising by hydrolysis, are essentially ineffective.It is concluded that heart mitochondria do contain a pore whose permeation state is controlled over an approximate 1000-fold range by Ca2 ' and other factors including phosphate, oxidative stress and ADP. The possible involvement of the pore in reoxygenation-induced injury in heart is discussed.It has long been known that isolated mitochondria become leaky on accumulation of excess Ca2+, especially in the presence of Pi and the absence of addcd adenine nucleotides, but the molecular basis of this phenomenon has remained obscure (review [l]). Measurements of light-scattering changes as an index of matrix shrinkage lead Haworth and Hunter [2, 31 to suggest the presence of a channel regulated by CaZf and nucleotides, although in our view those studies do not discriminate against the changes in mitochondrial conformation induced by nucleotides (Discussion) or against membrane damage and general leakiness. Ca2 +-induced leakiness could arise most conceivably via the action of Ca2+-dependent phospholipase A2, some of which is located on the matrix face of the inner membrane [4 -61. Indeed, Pfeiffer and co-workers [7, 81 (and references therein) subsequently provided evidence for cyclic deacylation/reacylation of membrane phospholipids, and they proposed that Ca2+-induced displacement of the cycle towards deacylation is the root cause of the increased nonspecific permeability caused by CaZ +. According to this model, the various agents that promote or inhibit the phenomenon do so by affecting the component enzymes of the cycle, viz phospholipase A2, acyl-CoA synthetase and lysophospholipid acyltransferase.

The mitochondrial permeability transition pore and its role in cell death

“…Subsequently a rapid-pulsedflow technique was used to measure ["%C]solute fluxes directly. There was an inverse relation between permeability and molecular size which, when analysed according to the Renkin equation, indicated a pore radius of 1.0-1.3 nm [30,31]. Since the hydrodynamic radius of poly(ethylene glycol) 1500 is about 1.2 nm [32], the two sets of measurement are in close agreement.…”

Outer mitochondrial membrane permeabilization: an open-and-shut case?

“…16 Concerning the size of the supramolecular openings, the nonselective nature of 10-2000 kDa dextran passage is more suggestive of large breaks in the OMM than the formation of discrete, tightly regulated pores. 17 Can resealing or fusion of outer (mitochondrial) membrane vesicles (OMVs) following dextran release be ruled out as an explanation for the absence of ultrastructural changes?…”

Mitochondrial Uncoupling Protein-4 Regulates Calcium Homeostasis and Sensitivity to Store Depletion-induced Apoptosis in Neural Cells

“…7, A and B). ROS are key inducers of mitochondrial permeability transition pore opening, and this process can trigger release of apoptogenic factors and activation of caspases (48). In addition to the mitochondrially derived ROS, expression of hUCP4 also blocked cPLA2 activation and subsequent oxidative metabolism of phospholipid-derived arachidonic acid via the cyclooxygenase or lipoxygenase pathways, which leads to O 2 .…”