The mitochondrial permeability transition pore (mPTP) opening plays a critical role in mediating cell death during ischemia/reperfusion (I/R) injury. Our previous studies have shown that cysteine 203 of cyclophilin D (CypD), a critical mPTP mediator, undergoes protein S-nitrosylation (SNO). To investigate the role of cysteine 203 in mPTP activation, we mutated cysteine 203 of CypD to a serine residue (C203S) and determined its effect on mPTP opening. Treatment of WT mouse embryonic fibroblasts (MEFs) with H(2)O(2) resulted in an 50% loss of the mitochondrial calcein fluorescence, suggesting substantial activation of the mPTP. Consistent with the reported role of CypD in mPTP activation, CypD null (CypD(-/-)) MEFs exhibited significantly less mPTP opening. Addition of a nitric oxide donor, GSNO, to WT but not CypD(-/-) MEFs prior to H(2)O(2) attenuated mPTP opening. To test whether Cys-203 is required for this protection, we infected CypD(-/-) MEFs with a C203S-CypD vector. Surprisingly, C203S-CypD reconstituted MEFs were resistant to mPTP opening in the presence or absence of GSNO, suggesting a crucial role for Cys-203 in mPTP activation. To determine whether mutation of C203S-CypD would alter mPTP in vivo, we injected a recombinant adenovirus encoding C203S-CypD or WT CypD into CypD(-/-) mice via tail vein. Mitochondria isolated from livers of CypD(-/-) mice or mice expressing C203S-CypD were resistant to Ca(2+)-induced swelling as compared with WT CypD-reconstituted mice. Our results indicate that the Cys-203 residue of CypD is necessary for redox stress-induced activation of mPTP.
"Previous studies have demonstrated that post-translational modifications of CyPD by phosphorylation and nitrosylation regulate PTP opening   . Other studies showed that CyPD can also be acetylated on lysine 166  . "
"Indeed, ablation of CyP-D renders the PTP insensitive to CsA and doubles the threshold Ca 2+ load required to open the PTP in the presence of phosphate anion (Pi)    . Notably, CyP-D can undergo several post-translation modifications, including phosphorylation , acetylation , and nitrosylation  ; CyP-D can also interact with a variety of proteins, such as Bcl-2 , the Ser/Thr kinase GSK-3 , the chaperones Hsp90, TRAP1  and Hsp60 , and the FOF1 ATP synthase . These dynamic changes of CyP-D affect the PTP, providing a remarkable level of flexibility in its modes of regulation. "
[Show abstract][Hide abstract] ABSTRACT: This review covers recent progress on the nature of the mitochondrial permeability transition pore (PTP) – a key effector in the mitochondrial pathways to cell death – and on the adaptive responses of tumor cells that desensitize the PTP to Ca2+ and reactive oxygen species (ROS), thereby playing an important role in the resistance of tumors to cell death. The discovery that the PTP forms from dimers of F-ATP synthase; and the definition of the Ca2+- and ROS-dependent signaling pathways affecting the transition of the F-ATP synthase from an energy-conserving to an energy-dissipating device open new perspectives for therapeutic intervention in cancer cells.
"For instance, Cys 39 nitrosylation in ND3 subunit of mitochondrial complex I has been associated with myocardial protection against ischemia/reperfusion injury . Cyclophilin D (CypD) oxidation at Cys 203 appears to be necessary for PTP opening related to oxidative stress . An additional relevant target of ROS is F O F 1 ATP synthase. "
[Show abstract][Hide abstract] ABSTRACT: Although mitochondrial dysfunction and oxidative stress have been proposed to play a crucial role in several types of muscular dystrophy (MD), whether a causal link between these two alterations exists remains an open question. We have documented that mitochondrial dysfunction through opening of the permeability transition pore plays a key role in myoblasts from patients as well as in mouse models of MD, and that oxidative stress caused by monoamine oxidases (MAO) is involved in myofiber damage. In the present study we have tested whether MAO-dependent oxidative stress is a causal determinant of mitochondrial dysfunction and apoptosis in myoblasts from patients affected by collagen VI myopathies. We find that upon incubation with hydrogen peroxide or the MAO substrate tyramine myoblasts from patients upregulate MAO-B expression and display a significant rise in reactive oxygen species (ROS) levels, with concomitant mitochondrial depolarization. MAO inhibition by pargyline significantly reduced both ROS accumulation and mitochondrial dysfunction, and normalized the increased incidence of apoptosis in myoblasts from patients. Thus, MAO-dependent oxidative stress is causally related to mitochondrial dysfunction and cell death in myoblasts from patients affected by collagen VI myopathies, and inhibition of MAO should be explored as a potential treatment for these diseases.
Free Radical Biology and Medicine 07/2014; 75. DOI:10.1016/j.freeradbiomed.2014.07.006 · 5.74 Impact Factor
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