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Inner Membrane Permeabilization – The Permeability Transition

Pathobiology of Human Disease, Page: 162-169
2014
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Book Chapter Description

Mitochondria perform essential functions in intermediary metabolism, energy conservation, intracellular Ca 2+ homeostasis, and cell death. Matrix substrate oxidation generates NADH and FADH 2, which, in the presence of oxygen, are reoxidized by the mitochondrial respiratory chain. Electron transfer within the respiratory complexes is accompanied by H + pumping from the matrix to the intermembrane space; since the inner membrane is almost impermeable to charged species, respiration thus creates a H + electrochemical gradient (Δ p ) that is used to transport ions and metabolites across the inner membrane and to synthesize ATP through the F 0 F 1 ATP synthase. ATP synthesis is not possible if the Δ p is dissipated by the occurrence of the Ca 2+ -dependent permeability transition, a permeability increase to ions and solutes caused by opening of a high-conductance channel, the permeability transition pore (PTP). PTP opening strictly requires matrix Ca 2+ – an essential ‘permissive’ factor – and is favored by a set of ‘inducers’ like inorganic phosphate. PTP opening is accompanied by depolarization, Ca 2+ release, matrix swelling, depletion of matrix pyridine nucleotides, rupture of the outer membrane, and release of intermembrane proteins including cytochrome c, apoptosis-inducing factor, and Smac/Diablo. These events contribute to cell death, and its mode – apoptosis versus necrosis – may depend on the fraction of mitochondria involved in the process and therefore on whether enough ATP can be provided for the apoptotic program to proceed. Here, we introduce the basic features of PTP regulation, discuss its molecular nature, and review disease processes in which PTP opening has a pathogenetic role, thus offering a novel target for therapy.

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