Two-hit hypothesis for mitochondrial Ca2+ in physiology and pathology. Under physiological conditions, Ca2+ is beneficial for mitochondrial function. However, in the presence of an overriding pathological stimulus, Ca2+ is detrimental. Similarly, Ca2+ can potentiate a subthreshold pathological stimulus, resulting in pathogenic consequences. See text for full explanation. [Ca2+]m, mitochondrial matrix Ca2+ concentration; ROS, reactive oxygen species.
Pathways of mitochondrial Ca2+ uptake and export. The respiratory chain is shown with (left to right) complexes I, III, IV, and V. The outer mitochondrial membrane and complex II are omitted for clarity. Where possible, known 3-dimensional (3D) structures obtained from the Protein Data Bank (http://www.rcsb.org/pdb) are shown. UP, Ca2+ uniporter; RaM, rapid-mode Ca2+ uptake; RyR, ryanodine receptor; PTP, permeability transition pore; Δψm, membrane potential.
The mitochondrial permeability transition pore. The putative components of the pore are shown, although the exact arrangement and stoichiometry are not known. Where possible, known 3D structures from the Protein Data Base are shown. In the case of cyclophilin D (Cyp-D), the structure of Cyp-A is shown. ANT, adenine nucleotide translocase; PBR, peripheral benzodiazepine receptor; VDAC, voltage-dependent anion channel; RSH, reduced thiol; RSSR, thiol disulfide.
Mechanisms for Ca2+ stimulation of mitochondrial ROS generation. Ca2+ stimulation of the TCA cycle (1) will enhance electron flow into the respiratory chain, and Ca2+ stimulation of nitric oxide synthase (NOS) and subsequent nitric oxide (NO·) generation (2) would inhibit respiration at complex IV (3). These events would enhance ROS generation from the Q cycle (4). In addition, NO· and Ca2+ can inhibit complex I, possibly enhancing ROS generation from this complex (5). Ca2+ also dissociates cytochrome c (cyt-c) from the inner membrane cardiolipin (6) and at high concentrations triggers PTP opening and cytochrome c release across the outer membrane (7). The subsequent inhibition at complex III (8) would enhance ROS generation at the Q cycle (4) Complex II is omitted from this diagram for clarity.
The mitochondrial Ca2+/ATP/ROS triangle. Solid arrows denote physiological effects; dotted arrows denote pathological effects. Words alongside the arrows describe specific events mediating the positive or negative effect. At the center of the triangle are factors that can orchestrate these effects. For full details, see text. SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase; ox-phos, oxidative phosphorylation; ER, endoplasmic reticulum; SR, sarcoplasmic reticulum; mRyR, mitochondrial RyR; IP3R, inositol 1,4,5-trisphosphate.
Mitochondria, Ca2+, and ROS in myocardial ischemia-reperfusion (I/R) injury. A: the events leading up to [Ca2+]m overload during I/R. Briefly, a drop in pH triggers Na+/H+ exchanger (NHE)-1-mediated Na+ influx, resulting in Na+ overload. Reverse-mode Na+/Ca2+ exchange across the plasma membrane (PM) then results in Ca2+ overload and subsequent [Ca2+]m overload. Ca2+ cycling across the mitochondrial membrane can lead to propagation and amplification of [Ca2+]m overload. In addition, ATP deficiency prevents adequate Ca2+ export by Ca2+-ATPases. B: cross-talk between the pathways of mitochondrial dysfunction, ROS, and Ca2+ overload in I/R injury. The precipitating events (boxes) are acidosis, elevated AMP, and ROS generation. A feed-forward loop is hypothesized, encompassing mitochondrial ROS generation, MAPKs, and [Ca2+]m overload. For further explanation, see text. RNS, reactive nitrogen species; AMPK, AMP-dependent protein kinase.
Mitochondria, Ca2+, and ROS in neuronal excitotoxicity. After N-methyl-d-aspartate receptor (NMDA-R)-mediated Ca2+ influx, the generation of both NO· and ROS elicits downstream cell death signaling. The relative importance of ROS from mitochondria and other sources is not fully understood. For further explanations, see text. nNOS, neuronal NOS; PARP, poly-ADP-ribose polymerase; GSH, reduced glutathione; AIF, apoptosis-inducing factor; XD, xanthine dehydrogenase; XO, xanthine oxidase.