Calcium signaling in cardiac mitochondria

Abstract

Mitochondrial Ca signaling contributes to the regulation of cellular energy metabolism, and mitochondria participate in cardiac excitation-contraction coupling (ECC) through their ability to store Ca, shape the cytosolic Ca signals and generate ATP required for contraction. The mitochondrial inner membrane is equipped with an elaborate system of channels and transporters for Ca uptake and extrusion that allows for the decoding of cytosolic Ca signals, and the storage of Ca in the mitochondrial matrix compartment. Controversy, however remains whether the fast cytosolic Ca transients underlying ECC in the beating heart are transmitted rapidly into the matrix compartment or slowly integrated by the mitochondrial Ca transport machinery. This review summarizes established and novel findings on cardiac mitochondrial Ca transport and buffering, and discusses the evidence either supporting or arguing against the idea that Ca can be taken up rapidly by mitochondria during ECC.

Fig. 1. Mitochondrial Ca transport and mitochondrial decoding of cytosolic Ca signals

A) Mitochondrial Ca uptake mechanisms and pathways located at the inner mitochondrial membrane (IMM). From left: RaM, rapid mode of Ca uptake; UCP2 and UCP3, uncoupling proteins 2 and 3; LETM1, leucine-zipper-EF-hand-containing transmembrane protein 1; mCa1 and mCa2, Ca-selective IMM conductances 1 and 2; MCU, mitochondrial Ca uniporter, with the associated protein MICU1; mRyR1, mitochondrial ryanodine receptor type 1; CoQ, Coenzyme Q10; ETC, electron transport chain. B) Mitochondrial Ca extrusion mechanisms and pathways located at the IMM. mPTP, mitochondrial permeability transition pore; mNCX, mitochondrial Na/Ca exchange with NCLX as suggested molecular identity; mHCX, mitochondrial proton/Ca exchange; mNHX, mitochondrial Na/proton exchange. C) Models of transmission of fast cytosolic Ca transients to matrix [Ca]_m: Model I, slow integration of cytosolic Ca spiking. Model II: rapid, beat-to-beat transmission of cytosolic Ca oscillations.

Fig. 2. Measurements of [Ca]_i to [Ca]_m transmission in single permeabilized ventricular myocytes

A) Technique used to simulate the effect of repetitive rapid cytosolic Ca transients on [Ca]_m. Mitochondria were loaded with the fluorescent Ca indicator fluo-3. Cells were placed in the laminar flow of Ca-free solution (1 mM EGTA) and exposed to computer controlled pressure ejections of a 100 µM Ca containing solution from a micropipette. B) Effect of Ca pulse duration (0.2, 0.5 and 1 s) on [Ca]_m at constant stimulation frequency (0.5 Hz). C) Effect of Ca pulse frequency (0.25 and 1 Hz) on [Ca]_m at constant pulse duration (0.5 s). (Panels A, B and C from Sedova, Dedkova & Blatter, Am. J. Physiol. Cell Physiol., 291(5): C840-50, 2006). D) [Ca]_m transients elicited by single Ca puffs applied at extended intervals. Extracellular [Na]_o (20 mM) was set to allow for maximal Ca extrusion rates via mNCX.