The mitochondrial outer membrane (OM) permeabilization leads to apoptotic protein release (Garrido et al., 2006; Green & Reed, 1998; Kroemer et al., 2007; Tsujimoto & Shimizu, 2007). The opening of the PT pore allows an influx of ions and water into mitochondrial matrix, inducing mitochondrial swelling (Henry-Mowatt, Dive, Martinou, & James, 2004). These reactions trigger the burst of mitochondrial outer membrane and the release of inter-membrane space (IM) proteins. The core proteins of permeability transition pore complex are a voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), and Cyclophilin D (CypD) (Schinzel et al., 2005). Other proteins, peripheral benzodiazepine receptor (PBR), hexokinase (HK), and creatine kinase (CK) are already known as the member of MPTPC (Song et al., 2011).The triggers of making MPTPC are the density of calcium, cell death signals and ROS, etc.
In mitochondria, ROS naturally generated by respiration is very tightly regulated by antioxidant as the defense mechanism. The PrxV is the one of the antioxidents in mitochondria and peroxisome in cytosol. In this study, PrxV were identified to associate with of CypD using MALDI TOF MS spectrometry analysis. In addition, PrxIII also exists in mitochondria and have same function against ROS generation. Interestingly, both of the PrxIII and PrxV bind to CypD in vitro system. The Prxs change their formation by oxidation and they can make diverse oligomeric conformations. On the basis of these studies, the binding capacity of mitochondrial Prxs against CypD may be different according to the ROS environment. Through the ITC, I confirm that the binding capacity of PrxV with CypD was increased on the status of oxidation environment. These results present the possibility of ROS dependent CypD modulator. For confirming the functions of mitochondrial Prxs, I designed siRNAs and decrease the mitochondrial membrane potential, dramatically. The point is that the reason of the decreasing membrane potential is not caused by ROS. It was confirmed by FACS data and I thought that the compensation effects against knock down of PrxV are arisen. In tumors, it is already known that the ROS level is higher than normal cell and the some types of tumors have the larger amount of PrxIII and V. I thought that the CypD is adequately inhibited by mitochondrial Prxs in normal cell condition. However, in tumors, the over-expressed Prxs authorizes tumor cells to resist high level of ROS condition by excessively inhibiting CypD. If the excessive ROS generation that was enough to oxidize PrxV are induced by anti-cancer drugs, PrxV dissociate itself from CypD for leading apoptosis (Figure 12).
Structural and functional transitions of mitochondria are associated with malignancy in much type of tumors. From these studies, as I assumed that the mitochondrial Prxs inhibit the CypD functions that make MPTPC and the development of mitochondrial Prxs targeted drugs can make synergetic effects
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through the combinational drug treatment which induce mitochondrial dependent cell death.
Figure 12. A Model Illustrating the Mechanism between CypD and PrxV.
As PrxV normally inhibit the CypD through direct but reversible binding, the MPTP is stably regulated. If the massive ROS generation is induced, PrxV is oxidized and it changes their conformation. The conformational change induces detachment of PrxV from CypD. The unlocked CypD get the more chance to make MPTP complex. In many cases, the diverse type of tumors overexpresses mitochondrial Prxs and generates high level of ROS in mitochondria. Even if the tumors are on the high level of ROS status, the MPTP opening is not induced. I suppose that the one of the mechanisms to resist high level of ROS condition in tumors is by overexpressing PrxV.
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