SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca²⁺ 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 Ca²⁺ microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca²⁺ 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 Ca²⁺ uptake is further optimized with the mitochondrial Ca²⁺ uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na⁺/Ca²⁺ exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca²⁺ from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca²⁺ concentrations oscillate in synchronicity with cytosolic Ca²⁺ transients during heartbeats. Proper Ca²⁺ 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 Ca²⁺ signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SR-mitochondrial Ca²⁺ signaling, research gaps, and future trends.