Cyclophilin D (CypD) is a mitochondrial immunophilin and a key positive regulator of the mitochondrial permeability transition (MPT). Several reports have shown that CypD is overexpressed in various tumors, where it has an anti-apoptotic effect. Because the MPT is a cell death-inducing phenomenon, we hypothesized that the anti-apoptotic effect of CypD is independent of the MPT but is due to its interaction with some key apoptosis regulator, such as Bcl2. Our data indicate that CypD indeed interacts with Bcl2 as confirmed with co-immunoprecipitation, pulldown, and mammalian two-hybrid assays. A cyclophilin D inhibitor, cyclosporine A, disrupts the CypD-Bcl2 interaction. CypD enhances the limiting effect of Bcl2 on the tBid-induced release of cytochrome c from mitochondria, which is not mediated via the MPT. Gain- and loss-of-function experiments confirm that CypD has a limiting effect on cytochrome c release from mitochondria and that such an effect of CypD is cyclosporine A- and Bcl2-dependent. On a cellular level, overexpression or knockdown of CypD respectively decreases or increases cytochrome c release from mitochondria and overall cell sensitivity to apoptosis progressing via the "intrinsic" pathway. Therefore, we here describe a novel function of CypD as a Bcl2 collaborator and an inhibitor of cytochrome c release from mitochondria independent of the MPT. This function of CypD may explain the anti-apoptotic effect of this protein observed in various cancer cells. The fact that some tumors overexpress CypD suggests that this may be an additional mechanism of suppression of apoptosis in cancer.
"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
"Likewise, interaction of CyP-D with Bcl2 has been shown to exert an anti-apoptotic effect, and CsA, disrupted the CyP-D-Bcl2 interaction. The anti-apoptotic effect of CyP-D in some cancer cells which overexpress the protein can be explained by CyP-D-Bcl2 interaction to suppress apoptosis in these cells (Eliseev et al., 2009). "
[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
"Recently , p53 was reported to accumulate in the mitochondrial matrix and trigger mitochondrial permeability transition pore (PTP) opening by interaction with the PTP regulatorcyclophilin D (CypD) in response to oxidative stress (Vaseva et al. 2012). Interestingly, BCL-2, which in some studies localizes preferentially at the inner mitochondrial membrane (Gotow et al. 2000) and not OMM, was show recently to also interact with matrix-localized Cyp D (Eliseev et al. 2009). Discrepancies between studies regarding the subcellular localization of different BCL-2 family proteins may reflect different cell types and energetic states, but may also reflect hereto unappreciated conformation-dependent epitopes recognized by different antibodies. "
[Show abstract][Hide abstract] ABSTRACT: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
Cold Spring Harbor perspectives in biology 02/2013; 5(2). DOI:10.1101/cshperspect.a008722 · 8.68 Impact Factor
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