Mitochondrial Ca2+ and regulation of the permeability transition pore

Abstract

The mitochondrial permeability transition pore was originally described in the 1970's as a Ca²⁺ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca²⁺ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca²⁺ in modulating the pore's open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca²⁺ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca²⁺ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/ nitrosylation of key residues. Lastly we introduce a novel view into how Ca²⁺ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.

Keywords: Calcium; Calpain; Cyclophilin D; Glycogen synthase kinase 3 Beta; Mitochondrial permeability transition pore; Reactive oxygen species.

Fig. 1

Models of the mPTP. A representative diagram of the proposed models of the mPTP through time. Where possible, known 3-dimensional (3D) structures obtained from the Protein Data Bank (http://www.rcsb.org/pdb) are shown. a. Classical model composed of BCL-2-associated-X-protein (BAX), Voltage Dependent Anion Channel (VDAC), the Perepheral Benzodiazepiene receptor (TSPO), Hexokinase II (HKII) on the Outer Mitochondrial Membrane (OMM), Mitochondrial Creatine Kinase (mtCK) in the intermembrane space, Adenine Nucleotide Transporter (ANT) in the inner mitochondrial membrane (IMM), and mitochondrial cyclophilin D (CypD) bound to ANT in the matrix. b. Phosphate Carrier model composed of BAX, VDAC, TSPO, HKII, mtCK, ANT, and CypD, bound to the phosphate carrier (PiC) c. Dimers of the F_oF₁ ATP Synthase. d. Uncoupling of the F_oF₁ ATP Synthase, and e. Spastic Paraplegia 7 composed of VDAC, and Glioblastoma Amplified Sequence (GBAS) on the OMM, Spastic Paraplegia 7 (SPG7) on the IMM, and matrix CypD bound to (SPG7)

Fig.2

Ca²⁺ as the central regulator of the mPTP. A representative diagram of the regulatory role of Ca²⁺ in the mitochondria. Where possible, known 3-dimensional (3D) structures obtained from the Protein Data Bank (http://www.rcsb.org/pdb) are shown. Thick solid lines denote proteins on which calcium exerts a direct effect. Thin lines are metabolic processes regulated by Ca²⁺, and dashed lines are processes that promote mPTP opening that are regulated by calcium. GSK-3β,Glycogen Synthase 3 Beta; CypD, mitochondrial Cyclophilin D; Cx I –V, Complex I –V; PDH, Pyruvate Dehydrogenase; CS Citrate Synthase; ACON, Aconitase; IDH, Isocitrate Dehydrogenase; α-KDH alpha Ketoglutarate Dehydrogenase; Fum, Fumarase; MDH, Malate Dehydrogenase; 2-ODH, 2-Oxoglutarate Dehydrogenase