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Review
. 2019 Mar 15:663:259-268.
doi: 10.1016/j.abb.2019.01.026. Epub 2019 Jan 24.

SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca2+ has a lot to say

Sergio De la Fuente  1 , Shey-Shing Sheu  2
Affiliations
Review

SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca2+ has a lot to say

Sergio De la Fuente et al. Arch Biochem Biophys. .

Abstract

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.

Keywords: Calcium; Heart; Mitochondria; Mitochondrial Ca(2+) uniporter; Mitofusin 2; SR-Mitochondria contacts.

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Conflict of interest statement

Disclosures

None.

Figures

Fig. 1.
Fig. 1.. Scheme of the components involved in the SR to mitochondria Ca2+ transfer.
The scheme shows a representation of the T-tubules, sarcoplasmic reticulum (junctional and network), and mitochondria, as well as all of the channels/transporters involved in the Ca2+ signaling: Ryanodine Receptor type 2 (RyR2), Mitochondrial Calcium Uniporter Complex (MCUC) preferentially located in the Junctional SR-mitochondria interface, mitochondrial Ryanodine Receptor type 1 (mRyR1), Rapid Mode of mitochondrial Ca2+ uptake (RaM), mitochondrial Permeability Transition Pore (mPTP), mitochondrial Na+/Ca2+ exchanger (NCLX) excluded from the junctional SR-mitochondria interface, mitochondrial H+/Ca2+ exchanger (mHCX, Letm1), and the SR-mitochondrial tethers MFN1/2. Other alternative SR-mito tethers are also represented. The solid red arrows represent the direction of the Ca+ fluxes.
Fig. 2.
Fig. 2.. Scheme of the ECB in normal SR-mito connections versus SR-mito disrupted connections.
The scheme shows a representation of the Ca2+ transfer from SR to mitochondria and mitochondrial processes that are regulated by variances in the [Ca2+]m. In normal conditions, the Ca2+ is appropriately transferred, enhancing NADH regeneration as well as the ATP production. In this situation ROS production is balanced, keeping ROS levels in a reasonable state and minimizing the chances of mPTP opening. In the absence of MFN2 (or other tethers), SR-mito communication is disrupted. The MCUC (and other Ca2+ influx mechanisms) cannot uptake Ca2+ properly from the Ca2+ microdomains, so the [Ca2+]m reached is low. NADH regeneration and ATP production cannot be adequately adjusted in the absence of Ca2+. ROS production is increased, however, it may not be enough to activate the opening of mPTP because of the low concentration of [Ca2+]m reached.
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