Peptidyl-prolyl cis-trans isomerase F (PPIF)

Peptidyl-prolyl cis-trans isomerase F (PPIF), commonly known as Cyclophilin D (CypD), is a mitochondrial matrix enzyme belonging to the cyclophilin family of peptidyl-prolyl isomerases [1, 4]. Its primary biological function is the regulation of the mitochondrial permeability transition pore (mPTP), a high-conductance channel in the inner mitochondrial membrane [1, 11, 18]. PPIF acts as a sensitizer for mPTP opening in response to calcium overload and oxidative stress, leading to mitochondrial dysfunction and cell death via necrosis or apoptosis [1, 14, 17]. Beyond mPTP regulation, PPIF functions as a molecular chaperone, catalyzing the cis-trans isomerization of proline imidic peptide bonds to facilitate proper protein folding [4, 7, 13]. In pathological states, PPIF-mediated mPTP opening is a critical driver of tissue damage in ischemia-reperfusion injury, neurodegenerative disorders like Alzheimer’s disease, and muscular dystrophies [4, 11, 14, 18]. PPIF is also implicated in cancer progression, where it may modulate tumor cell bioenergetics and survival [2, 17]. As a therapeutic target, PPIF is inhibited by drugs such as Cyclosporine A and its non-immunosuppressive analogs like Alisporivir, which bind to the enzyme's active site to prevent mPTP activation [1, 11, 14]. Therapeutic challenges include achieving isoform selectivity to avoid off-target effects on other cyclophilins and managing the potential disruption of physiological mitochondrial signaling [11, 17].

Other names

Cyclophilin DCypDCyclophilin 3CYP3CyP-MMitochondrial cyclophilinPPIase FRotamase F

Inhibition of the mitochondrial permeability transition pore (mPTP) opening by binding to the PPIase active site of PPIF, thereby increasing the threshold for calcium-induced pore activation [1, 11, 14, 18].