Cyclophilin D

Cyclophilin D

Cyclophilin D (CypD) is a mitochondrial matrix protein that plays a crucial role in the regulation of the mitochondrial permeability transition pore (mPTP). It is a member of the cyclophilin family of peptidyl-prolyl isomerases, which are enzymes that catalyze the cis-trans isomerization of proline imidic peptide bonds in proteins, facilitating protein folding.

Structure

Cyclophilin D is encoded by the PPIF gene in humans. The protein consists of a single domain that is characteristic of cyclophilins, which includes a conserved region responsible for its peptidyl-prolyl isomerase activity. The structure of Cyclophilin D allows it to interact with other components of the mPTP, such as the adenine nucleotide translocase (ANT) and the voltage-dependent anion channel (VDAC).

Function

Cyclophilin D is primarily located in the mitochondrial matrix, where it regulates the opening of the mPTP. The mPTP is a non-specific channel that spans the inner mitochondrial membrane and is involved in the regulation of mitochondrial membrane potential and cell death pathways. Under normal physiological conditions, the mPTP remains closed, but it can open in response to increased calcium levels, oxidative stress, or other pathological stimuli.

The opening of the mPTP leads to the loss of mitochondrial membrane potential, swelling of the mitochondria, release of pro-apoptotic factors, and ultimately cell death. Cyclophilin D modulates the sensitivity of the mPTP to these stimuli, and its inhibition has been shown to protect against cell death in various models of ischemia-reperfusion injury and neurodegenerative diseases.

Clinical Significance

Cyclophilin D has been implicated in a variety of diseases, including cardiovascular disease, neurodegenerative disorders, and cancer. Inhibition of Cyclophilin D has been proposed as a therapeutic strategy to prevent cell death in conditions such as myocardial infarction and stroke. Additionally, Cyclophilin D is a target for the immunosuppressive drug cyclosporine, which binds to cyclophilins and inhibits their isomerase activity.

Research

Recent studies have focused on the development of specific inhibitors of Cyclophilin D that do not affect other cyclophilins, in order to minimize side effects. The role of Cyclophilin D in the regulation of mitochondrial dynamics and its interaction with other mitochondrial proteins is an active area of research.

Also see

• Mitochondrial permeability transition pore
• Peptidyl-prolyl isomerase
• Mitochondria
• Cell death
• Cyclosporine