Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore

Abstract

This review focuses on the role of cyclophilin D (CypD) as a prominent mediator of the mitochondrial permeability transition pore (MPTP) and subsequent effects on cardiovascular physiology and pathology. Although a great number of reviews have been written on the MPTP and its effects on cell death, we focus on the biology surrounding CypD itself and the non-cell death physiologic functions of the MPTP. A greater understanding of the physiologic functions of the MPTP and its regulation by CypD will likely suggest novel therapeutic approaches for cardiovascular disease, both dependent and independent of programmed necrotic cell death mechanisms.

Figure 1.. CypD interactors and physiological regulators of the MPTP.

Various molecular components of the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) have been proposed to form the large, non-specific mitochondrial permeability transition pore (MPTP). Upon formation the passage of solutes ≤ 1.5 kD in size cross the IMM resulting in organelle swelling and eventual rupture, a key event in necrotic cell death. Calcium (Ca²⁺), the most noted mediator of permeability transition, enters the matrix via the mitochondrial calcium uniporter complex (MCU and MCUR1) driven by the highly negative membrane potential (ΔΨ). Reactive oxygen species (ROS) increase MPTP open probability while adenine nucleotides (ADP and ATP) inhibit pore formation. Inorganic phosphate (P_i) while traditionally viewed as an activator of MPTP may have a dual role as an inhibitor under appropriate conditions. (key is lower left). Additional abbreviations not used in text: HK II, hexokinase-II; ATPase, F1/F0 ATPase.

Figure 2.. MPTP-mediated mitochondrial calcium (_mitoCa²⁺) Efflux.

The flow chart details a possible physiological function for the MPTP in maintaining _mitoCa²⁺ homeostasis in the heart during times of stress. Low-conductance or transient opening of the pore may represent an important route of Ca²⁺ extrusion from the matrix. (left side, black arrows = homeostatic conditions, right side, red arrows = pathological conditions).