Cyclophilin D as a Drug Target

Abstract

The mitochondrial permeability transition (MPT) plays an important role in damage-induced cell death, and agents inhibiting the MPT may have a therapeutic potential for treating human conditions such as ischemia/reperfusion injury, trauma, and neurodegenerative diseases. The mitochondrial matrix protein, cyclophilin D (CYP D), a member of a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases), plays a decisive role in MPT, being an integral constituent of the MPT pore. Other putative MPT pore proteins include the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC). In an alternative model, the MPT pore is formed by clusters of misfolded membrane proteins outlining aqueous channels that are regulated by CYP D and other chaperone-like proteins. Like cyclophilin A (CYP A) and other cyclophilin family members, CYP D is targeted by the immunosuppressant cyclosporin A (CsA). CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A. The relevance of MPT inhibition by CsA for its cytoprotective effects is well documented in many cellular models. Mechanisms of action in vivo are more difficult to define, and accordingly the evidence is as yet less compelling in in vivo animal models of ischemia/reperfusion injury, trauma and neurodegenerative diseases. Notwithstanding, CYP D is a drug target of high interest. Structural considerations suggest feasibility of designing CYP D ligands without immunosuppressant properties. This is highly desirable, since they have the potential of being useful therapeutic agents in a variety of disease states. It might be a tougher challenge to obtain compounds specific for CYP D vs. other cyclophilins, and/or of small molecular weight, allowing brain penetration to make them suitable for treating neurodegenerative diseases.

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

“…CsA is however not specific for mPT since it also inhibits calcineurin (unlike the non-immunosuppressive analogs tested in the present study) and nonmitochondrial cyclophilins, and CsA has not consistently provided cytoprotection in cellular models of glutamate excitotoxicity [44]. CsA and its non-immunosuppressive analogs have however more robustly mediated neuroprotection in animal models of global and focal cerebral ischemia, traumatic brain injury and amyotrophic lateral sclerosis when means are taken to deliver the drug to the central nervous system [25,45]. More specific evidence for the involvement of mPT in neurological disorders has more recently been obtained with genetically modified mice lacking cyclophilin D, an important modulator of the mPT and the mitochondrial receptor for CsA.…”

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…However, NIM811 protects against tumor necrosis factor-α-induced apoptosis, spanning a much wider concentration range compared to CsA [113]. The cytoprotective properties of NIM811 against apoptotic stimuli have also been reported in other cell types [113,114,121,122]. Therefore, the unique properties of NIM811 allows for testing of a broader dose range relative to CsA.…”

“…NIM811 (N-methyl-isoleucine-cyclosporin) is a cyclosporin analog that also binds to Cyp-D and blocks mPT at nanomolar concentrations in brain mitochondria [112][113][114]. NIM811 was originally developed to be a less toxic alternative to CsA, but the modifications made to the cyclosporin structure eliminated the immunosuppressive properties mediated by calcineurin inhibition.…”

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

“…12,13 In addition to its immunosuppressive action, CsA inhibits the mitochon-drial permeability transition (MPT), a phenomenon characterized by mitochondrial swelling, uncoupling, and inner membrane permeabilization to solutes of molecular mass up to 1500 Da. 14 The MPT is implicated in lethal cell injury from anoxia, ischemia/reperfusion, and oxidative stress to liver, heart, and other cell types. 15 Increased Ca 2ϩ and reactive oxygen and nitrogen species activate the MPT, whereas CsA inhibits it.…”