SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca has a lot to say.

In adult cardiomyocytes, T-tubules, junctional sarcoplasmic reticulum (jSR), and mitochondria juxtapose each other and form a unique and highly repetitive functional structure along the cell. The close apposition between jSR and mitochondria creates high Ca microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca transfer from SR to mitochondria plays a critical role. The SR-mitochondria contacts are established through protein tethers, with mitofusin 2 the most studied SR-mitochondrial "bridge", albeit controversial. Mitochondrial Ca uptake is further optimized with the mitochondrial Ca uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na/Ca exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca concentrations oscillate in synchronicity with cytosolic Ca transients during heartbeats. Proper Ca transfer controls not only the process of mitochondrial bioenergetics, but also of mitochondria-mediated cell death, autophagy/mitophagy, mitochondrial fusion/fission dynamics, reactive oxygen species generation, and redox signaling, among others. Our review focuses specifically on Ca signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SR-mitochondrial Ca signaling, research gaps, and future trends.