An article recently published in Cell concluded that p53 is necessary and sufficient to induce mitochondrial permeability transition pore (MPTP)-dependent necrosis through inducible p53 translocation to the matrix with cyclophilin D (CypD) binding. The results and implications are very provocative. The physiological significance of the proposed paradigm, however, is uncertain because calcium itself, which is a fundamental regulator of MPTP, is independent of p53, as shown by the authors. In addition, purified mitochondria from any unstimulated cell type or tissue, which presumably lacks p53 given the inducible mechanism proposed, have a fully functional MPTP to all the classic modes of stimulation as analyzed in vitro.
"Furthermore, CyPD phosphorylation (Rasola et al., 2010), acetylation (Shulga and Pastorino, 2010), and nitrosylation (Kohr et al., 2011; Nguyen et al., 2011) affect the propensity of the PTP to open (Rasola and Bernardi, 2011). Not surprisingly CyPD may interact with many proteins including Hsp90 and its related molecule TRAP-1 (Kang et al., 2007); Bcl-2 (Eliseev et al., 2009); ERK-2/GSK-3 (Rasola et al., 2010); possibly p53 (Vaseva et al., 2012), but see (Karch and Molkentin, 2012); and the F O F 1 ATP synthase (Giorgio et al., 2009). The latter interaction turned out to be the key for identification of the PTP. "
[Show abstract][Hide abstract] ABSTRACT: The permeability transition (PT) denotes an increase of the mitochondrial inner membrane permeability to solutes with molecular masses up to about 1500 Da. It is presumed to be mediated by opening of a channel, the permeability transition pore (PTP), whose molecular nature remains a mystery. Here I briefly review the history of the PTP, discuss existing models, and present our new results indicating that reconstituted dimers of the FOF1 ATP synthase form a channel with properties identical to those of the mitochondrial megachannel (MMC), the electrophysiological equivalent of the PTP. Open questions remain, but there is now promise that the PTP can be studied by genetic methods to solve the large number of outstanding problems.
Frontiers in Physiology 05/2013; 4(1):95. DOI:10.3389/fphys.2013.00095 · 3.53 Impact Factor
"However, the study demonstrated no regulation of calcium-dependent MPTP opening by p53. It is not clear how p53-CyP-D interaction senses and induces mPTP opening in a Ca2+-independent manner (Karch and Molkentin, 2012). Notably, binding of CyP-D to a matrix protein in cancer cells may have an opposite effect, leading to inhibition of the mPTP. "
[Show abstract][Hide abstract] ABSTRACT: Mitochondria serve as a "powerhouse" which provides near 90% of ATP necessary for cell life. However, recent studies provide strong evidence that mitochondria also play a central role in cell death. Mitochondrial permeability transition (mPT) at high conductance in response to oxidative or other cellular stresses is accompanied by pathological and non-specific mPT pore (mPTP) opening in the inner membrane of mitochondria. Mitochondrial PTP can serve as a target to prevent cell death under pathological conditions such as cardiac and brain ischemia/reperfusion injury and diabetes. On the other hand, mPTP can be used as an executioner to specifically induce cell death thus blocking tumorigenesis in cancer diseases. Despite many studies, the molecular identity of the mPTP remains unclear. Cyclophilin D (CyP-D) plays an essential regulatory role in pore opening. This review will discuss direct and indirect mechanisms underlying CyP-D interaction with a target protein of the mPTP complex. Understanding of the mechanisms of mPTP opening will be helpful to further develop new pharmacological agents targeting mitochondria-mediated cell death.
Frontiers in Physiology 04/2013; 4:76. DOI:10.3389/fphys.2013.00076 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress-induced neuronal cell death requires opening of the mitochondrial permeability transition pore. P53 mitochondrial translocation and association with Cyclophilin D (Cyp-D) is required for the pore opening. Here we tested this signaling axis in oxygen glucose deprivation (OGD)/re-oxygenation-induced in vitro neuronal death. Using mitochondrion immunoprecipitation, we found that p53 translocated to mitochondrion and associated with Cyp-D in SH-SY5Y cells exposed to (OGD)/re-oxygenation. Disruption of this complex by Cyp-D inhibitor Cyclosporine A (CsA), or by Cyp-D or p53 deficiency, significantly inhibited OGD/re-oxygenation-induced apoptosis-independent cell death. Conversely, over-expression of Cyp-D in SH-SY5Y cells caused spontaneous cell death, and these cells were more vulnerable to OGD/re-oxygenation. Finally, CsA or Cyp-D RNAi suppressed OGD/re-oxygenation-induced neuronal cell death in primary cultures. Together, our study suggests that OGD/re-oxygenation-induced in vitro cell death involves a mitochondrial Cyp-D/p53 signaling axis.
Neurochemical Research 01/2013; 38(4). DOI:10.1007/s11064-013-0968-5 · 2.59 Impact Factor
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