| Cyclophilin F, also known as peptidyl‑prolyl cis‑trans isomerase F (PPIF), is a mitochondrial member of the cyclophilin immunophilin family that catalyzes cis–trans isomerization of proline imidic peptide bonds and acts as a foldase and chaperone within the matrix, while also serving as a key regulator of mitochondrial permeability transition, ATP synthase function and cell death signaling. The protein adopts the conserved cyclophilin fold of eight antiparallel β‑strands forming a β‑barrel flanked by α‑helices, with a hydrophobic and positively charged active‑site pocket that binds proline‑containing substrates and the immunosuppressive drug cyclosporin A, and structural characterization of human mitochondrial cyclophilins demonstrates that substrate recognition and catalysis rely on conserved residues that stabilize the transition state and accelerate conformational rearrangements in client proteins. Cyclophilin F associates with components of the mitochondrial permeability transition pore (mPTP) at the inner membrane, and its interaction with pore elements modulates open probability in response to calcium, reactive oxygen species and inorganic phosphate; cyclosporin A binding to Cyclophilin F inhibits pore opening, decreases mitochondrial swelling and protects against necrotic and apoptotic stimuli, supporting a model in which Cyclophilin F acts as a modulatory factor whose PPIase‑dependent or ‑independent interactions with mPTP components govern threshold and kinetics of permeability transition. Beyond mPTP control, Cyclophilin F participates in the regulation of mitochondrial F1F0‑ATP synthase activity and matrix adenine nucleotide levels, influencing proton‑transporting ATPase function and coupling efficiency, and it has been reported to exert anti‑apoptotic effects independently of mPTP by cooperating with BCL2 to inhibit cytochrome c‑dependent apoptosis and negative regulation of intrinsic apoptotic signaling pathways, linking its chaperone and signaling roles directly to mitochondrial outer membrane permeabilization and caspase activation. Under oxidative stress, Cyclophilin F forms complexes with mitochondrial p53, and this cooperation promotes programmed necrotic cell death by enhancing mPTP opening and mitochondrial depolarization, illustrating that Cyclophilin F can participate in both survival and death pathways depending on its binding partners and post‑translational context. Human cyclophilins as a group are increasingly recognized as drug targets in cardiovascular disease, neurodegeneration, viral infection and cancer, and emerging reviews highlight that mitochondrial cyclophilins such as Cyclophilin F are involved in oxidative stress responses, ischemia–reperfusion injury and inflammatory signaling, making their active sites and cyclosporin‑binding surfaces attractive for small‑molecule modulation of mPTP and mitochondrial resilience. |
