The mitochondrial permeability transition pore and its role in cell death

Abstract

This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke ‘accidental’ apoptosis.

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

“…In addition, CKMT1 has been implicated in the regulation of the Ca 2 þ -induced mitochondrial permeability transition pore (PTP; O'Gorman et al, 1997). PTP is involved in triggering apoptosis by releasing proapoptotic factors into the cytosol (Crompton, 1999). Several studies have shown the aberrant expression of CKMT1 in cancers of various organs, including lung cancer, breast cancer, gastric cancer, colon cancer, and prostate cancer (DeLuca et al, 1981;Tsung, 1983;Kanemitsu et al, 1984;Wallimann et al, 1992), suggesting that CKMT1 is involved in the pathogenesis of various cancers.…”

A review of neurotoxicity of microcystins

“…Neurotransmitters released from adjacent neurons can generate slow depolarizing junctional potential which then can elicit an action potential through activating and then deactivating sodium-selective and potassium channels (Florczyk et al 2014). The voltage-dependent anion channel (VDAC) can assist the mitochondria with controlling cell death through releasing calcium, cytochrome c, and apoptosis-inducing factor from the mitochondria inner membrane space (Crompton 1999;Tsujimoto and Shimizu 2002). The coordination of Ca 2+ channels and Na + channels plays a vital role in regulating signal transduction pathways, including cell cycle and apoptosis.…”

The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

“…In general, mitochondrial Ca 2+ overload and consequent mitochondrial dysfunction appear to be combining factors in excitotoxicity. They are playing key roles in cell death [64]. …”