Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart

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 2+ microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca 2+ 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 2+ uptake is further optimized with the mitochondrial Ca 2+ uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na + /Ca 2+ exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca 2+ from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca 2+ concentrations oscillate in synchronicity with cytosolic Ca 2+ transients during heartbeats. Proper Ca 2+ 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 2+ signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SRmitochondrial Ca 2+ signaling, research gaps, and future trends.

Intracellular Ca 2+ signals are well organized in all cell types, and trigger a variety of vital physiological processes. The temporal and spatial characteristics of cytosolic Ca 2+ increases are mainly governed by the fluxes of this ion across the membrane of the endoplasmic/sarcoplasmic reticulum and the plasma membrane. However, various Ca 2+ transporters also allow for Ca 2+ exchanges between the cytoplasm and mitochondria. Increases in mitochondrial Ca 2+ stimulate the production of ATP, which allows the cells to cope with the increased energy demand created by the stimulus. Less widely appreciated is the fact that Ca 2+ handling by mitochondria also shapes cytosolic Ca 2+ signals. Indeed, the frequency, amplitude, and duration of cytosolic Ca 2+ increases can be altered by modifying the rates of Ca 2+ transport into, or from, mitochondria. In this review, we focus on the interplay between mitochondria and Ca 2+ signaling, highlighting not only the consequences of cytosolic Ca 2+ changes on mitochondrial Ca 2+ , but also how cytosolic Ca 2+ dynamics is controlled by modifications of the Ca 2+ -handling properties and the metabolism of mitochondria.

Heart failure (HF) represents one of the leading causes of cardiovascular diseases with high rates of hospitalization, morbidity and mortality worldwide. Ample evidence has consolidated a crucial role for mitochondrial injury in the progression of HF. It is well established that mitochondrial Ca 2+ participates in the regulation of a wide variety of biological processes, including oxidative phosphorylation, ATP synthesis, reactive oxygen species (ROS) generation, mitochondrial dynamics and mitophagy. Nonetheless, mitochondrial Ca 2+ overload stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling, resulting in mitochondrial injury, apoptosis, cardiac remodeling, and ultimately development of HF. Moreover, mitochondria possess a series of Ca 2+ transport influx and efflux channels, to buffer Ca 2+ in the cytoplasm. Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca 2+ homeostasis and plays an essential role in the progression of HF. Here, we provide an overview of regulation of mitochondrial Ca 2+ homeostasis in maintenance of cardiac function, in an effort to identify novel therapeutic strategies for the management of HF.