Peptidyl-prolyl cis-trans isomerase F (Cyclophilin D) (CypD)

Peptidyl-prolyl cis-trans isomerase F, commonly known as Cyclophilin D (CypD), is a protein located within the mitochondrial matrix that serves as the primary regulatory component of the mitochondrial permeability transition pore (mPTP) (UniProt: P30405). The mPTP is a high-conductance channel whose opening leads to mitochondrial swelling, loss of membrane potential, and the release of pro-apoptotic factors, ultimately causing cell death via necrosis or apoptosis (PubMed: 26337120). CypD functions as a molecular chaperone and isomerase that facilitates the conformational changes necessary for pore opening, particularly under conditions of calcium overload and oxidative stress (PubMed: 15744310). Genetic deletion or pharmacological inhibition of CypD has been shown to protect tissues from ischemia-reperfusion injury in the heart and brain, as well as slow the progression of neurodegenerative diseases like Alzheimer's (PubMed: 15744299, PubMed: 17554305). Drugs such as Cyclosporine A target CypD to prevent mPTP opening, although their clinical use is limited by immunosuppressive effects mediated through other cyclophilins (PubMed: 21660030). Consequently, non-immunosuppressive CypD inhibitors like Alisporivir are being investigated for their potential to treat mitochondrial-related pathologies (PubMed: 25533411).

Other names

PPIFPeptidyl-prolyl isomerase FMitochondrial cyclophilinCyp-DRotamase FMatrix cyclophilin

Inhibition of the peptidyl-prolyl isomerase activity of Cyclophilin D (CypD) prevents its interaction with the mitochondrial permeability transition pore (mPTP) complex, thereby increasing the threshold of mitochondrial calcium required to trigger pore opening and protecting the cell from necrotic death (PubMed: 15744310).