Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore

• Published in: Biochimica et biophysica acta Vol. 1850; no. 10; pp. 2041 - 2047
• Main Authors: Gutiérrez-Aguilar, Manuel, Baines, Christopher P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2015
• Subjects: Animals; catalysts; catalytic activity; Cyclophilin-D; cyclophilins; Cyclophilins - chemistry; Cyclophilins - metabolism; disease control; drugs; Humans; ligands; mitochondria; Mitochondrial Membrane Transport Proteins - chemistry; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial permeability transition; Peptidyl-prolyl cis-trans isomerase; permeability; phenotype; post-translational modification; Protein Processing, Post-Translational - physiology; Structure-Activity Relationship; Mitochondrial permeability transition; Peptidyl-prolyl cis-trans isomerase; ANT; CypA; PTM; GST; CypD; PiC; GSNO; MCC; PDB; CsA; MPT; Cyclophilin-D; OSCP; CsABD; VDAC; PAO
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.11.009

Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dysfunction 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. This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore. 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. 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.