Is p53 the Long-Sought Molecular Trigger for Cyclophilin D-Regulated Mitochondrial Permeability Transition Pore Formation and Necrosis?
ABSTRACT 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.
SourceAvailable from: Muhammad Rizwan Alam[Show abstract] [Hide abstract]
ABSTRACT: Reperfusion is characterized by a deregulation of ion homeostasis and generation of reactive oxygen species that enhance the ischemia-related tissue damage culminating in cell death. The mitochondrial permeability transition pore (mPTP) has been established as an important mediator of ischemia-reperfusion (IR)-induced necrotic cell death. Although a handful of proteins have been proposed to contribute in mPTP induction, cyclophilin D (CypD) remains its only bona fide regulatory component. In this review we summarize existing knowledge on the involvement of CypD in mPTP formation in general and its relevance to cardiac IR injury in specific. Moreover, we provide insights of recent advancements on additional functions of CypD depending on its interaction partners and post-translational modifications. Finally we emphasize the therapeutic strategies targeting CypD in myocardial IR injury.Journal of Molecular and Cellular Cardiology 10/2014; DOI:10.1016/j.yjmcc.2014.09.026 · 5.22 Impact Factor
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ABSTRACT: The mitochondrial permeability transition (PT) -an abrupt increase permeability of the inner membrane to solutes- is a causative event in ischemia-reperfusion injury of the heart, and the focus of intense research in cardioprotection. The PT is due to opening of the PT pore (PTP), a high conductance channel that is critically regulated by a variety of pathophysiological effectors. Very recent work indicates that the PTP forms from the F-ATP synthase, which would switch from an energy-conserving to an energy-dissipating device. This review provides an update on the current debate on how this transition is achieved, and on the PTP as a target for therapeutic intervention.Journal of Molecular and Cellular Cardiology 09/2014; 78. DOI:10.1016/j.yjmcc.2014.09.023 · 5.22 Impact Factor
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ABSTRACT: Background: Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dys-function during diverse pathological situations. Although this bioenergetic entity has been studied extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease. Scope of review: This review aims to recapitulate known molecular determinants necessary for Cyclophilin D ac-tivity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore. Major conclusions: While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post-translational modifications of this isomerase and its catalytic activity facilitates pore opening. General significance: Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.Biochimica et Biophysica Acta (BBA) - General Subjects 11/2014; 14(S0304-4165):00386. DOI:10.1016/j.bbagen.2014.11.009 · 3.83 Impact Factor