Mitochondria in cardiomyocyte Ca2+ signaling.

Ca(2+) signaling is of vital importance to cardiac cell function and plays an important role in heart failure. It is based on sarcolemmal, sarcoplasmic reticulum and mitochondrial Ca(2+) cycling. While the first two are well characterized, the latter remains unclear, controversial and technically challenging. In mammalian cardiac myocytes, Ca(2+) influx through L-type calcium channels in the sarcolemmal membrane triggers Ca(2+) release from the nearby junctional sarcoplasmic reticulum to produce Ca(2+) sparks. When this triggering is synchronized by the cardiac action potential, a global [Ca(2+)](i) transient arises from coordinated Ca(2+) release events. The ends of intermyofibrillar mitochondria are located within 20 nm of the junctional sarcoplasmic reticulum and thereby experience a high local [Ca(2+)] during the Ca(2+) release process. Both local and global Ca(2+) signals may thus influence calcium signaling in mitochondria and, reciprocally, mitochondria may contribute to the local control of calcium signaling. In addition to the intermyofibrillar mitochondria, morphologically distinct mitochondria are also located in the perinuclear and subsarcolemmal regions of the cardiomyocyte and thus experience a different local [Ca(2+)]. Here we review the literature in regard to several issues of broad interest: (1) the ultrastructural basis for mitochondrion - sarcoplasmic reticulum cross-signaling; (2) mechanisms of sarcoplasmic reticulum signaling; (3) mitochondrial calcium signaling; and (4) the possible interplay of calcium signaling between the sarcoplasmic reticulum and adjacent mitochondria. Finally, this review discusses experimental findings and mathematical models of cardiac calcium signaling between the sarcoplasmic reticulum and mitochondria, identifies weaknesses in these models, and suggests strategies and approaches for future investigations.