The interplay between mitochondria and store‐operated Ca²⁺ entry: Emerging insights into cardiac diseases

Figures

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  FIGURE 1. STIM1 oligomerizes to activate SOCE in the heart upon stress stimulation. Upon agonist stimulation of its receptor (GPCRs), Phospholipase C (PLC) is activated by GPCRs and subsequently promote the liberating of IP3 from PIP2. IP3 binds to its receptor (IP3R) to facilitate Ca2+ release from the endoplasmic reticulum ER lumen. These events lead to decreased Ca2+ concentration in ER and ensuing oligomer formation of STIM1; then, STIM1 oligomers bind to SOCE channels, such as Orai1, to promote Ca2+ influx. SERCA pumps are also concentrated around STIM1 oligomers for re‐uptaking influx Ca2+ through SOCE channels. Such an organization will avoid massive diffusion of Ca2+ ions in the cytosol, and Ca2+ are re‐uptaken by the pumps as soon as they reach the cytosol

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  FIGURE 2. The spatial distribution of the mitochondrial network and CCM in cardiomyocytes. In cardiomyocytes, mitochondria are separated by muscle filaments and are mainly divided into sub‐PM mitochondria and interfibrillar mitochondria. But mitochondria can still be connected through inter‐mitochondrial junction (IMJ) to form a mitochondrial network. IMJ promotes the exchange of metabolites and mitochondrial DNA among independent mitochondria and inhibits the transmission of stress in the mitochondrial network. Sub‐PM mitochondria are close to the SOCE channels and mediate Ca2+ uptake through the activation of MCU. There are two different types of CCM in cardiomyocytes: The first CCM is mediated by DHPR/RyR2 and is located near the muscle filament deep in the cytoplasm, promoting the contraction of cardiomyocytes. DHPR/ RyR2‐mediated CCM can be rapidly dissipated through SERCA and NCX activation, thus allowing cardiomyocytes to enter the diastolic phase. DHPR/RyR2‐mediated CCM is consistent with excitatory contraction coupling of cardiomyocytes and occurs periodically. Abbreviations: CCM, calcium concentration microdomains; DHPR, dihydropyridine receptor; IMJ, inter‐mitochondrial…

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  FIGURE 3. Mitochondria are closely related to SOCE during the development of cardiac hypertrophy. Hypertrophy related cardiac stress promotes the opening of IP3R, then releases Ca2+ from ER to initiate SOCE. SOCE‐induced Ca2+ influx promotes calcineurin‐dependent de‐phosphorylation (De‐p) of NFAT; this calcineurin‐NFAT signalling upregulates the expression of hypertrophy related genes. Positive feedback between mitochondria and SOCE may exist due to NF‐kB activation: mtROS activate NF‐kB to increase the transcriptional activity of Orai1 and STIM1, in turn, improved SOCE machinery further elevate mitochondrial Ca2+ uptake to generate mtROS. Diminished FAO and enhanced glucose oxidation cause inefficiency of the TCA cycle, leading to a decrease in ATP production and the ensuing increase in AMPK activation. AMPK negatively regulated SOCE activation through STIM1 phosphorylation and Nedd4‐2 dependent Orai1 degradation. NF‐kB facilitates whilst AMPK attenuates SOCE activity, suggesting that the regulatory pattern of mitochondria on SOCE activity is biphasic in hypertrophic heart. De‐P denotes de‐phosphorylation; P denotes phosphorylation

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  FIGURE 4. Mitochondria and SOCE are reciprocally regulated following I/R. I/R injury of the heart is characterised by Ca2+ overload and a burst of mtROS generation at the onset of reperfusion. For Ca2+ overload, SOCE is a major contributor which may result from the enhanced capability of mitochondrial Ca2+ uptake by MCU: mitochondrial Ca2+ uptake reduces the size of CCMs in the proximity of Ca2+ entry sites and protects SOCE channels from Ca2+‐dependent inactivation; mitochondria take up Ca2+ through IP3R to maintain a low concentration of Ca2+ in ER to activate SOCE. Besides, upregulated Mfn2 tether mitochondria and ER together, making IP3R and MCU at a close distance, resulting in a persistent Ca2+ transport from ER to mitochondria and sustained activation of SOCE. Mfn2 is also important for translocation of STIM1 to ER‐PM junction sites where STIM1 interact with and activate SOCE channels. For mtROS generation, SOCE‐induced [Ca2+]m accumulation (in MCU‐dependent manner) is a major contributor, which is also referred to as SOCE‐[Ca2+]m‐mtROS pathway. SOCE‐[Ca2+]m‐mtROS pathway sensitises ER to release Ca2+ to stabilise the opening of SOCE channels during the I/R process. Mitochondrial…

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  FIGURE 5. Mitochondria and SOCE are reciprocally regulated in diabetic cardiomyopathy. Hyperglycaemia mediated STIM1 O‐GlcNAcylation decrease SOCE activity. In diabetic cardiomyocytes, impairment of glucose metabolism and compensatory increased FFA metabolism increase UCP2 activity and subsequently decrease ATP production; due to altered protein levels and activity of mitochondrial dynamic‐related proteins (OPA1, Mfn2, and Drp1), the pro‐fission activity of mitochondria is highly active in diabetic cardiomyocytes, resulting in decreased Δψ and ATP content. Decreased ATP could not effectively buffer CCMs in the proximity of Ca2+ entry sits and subsequently facilitate Ca2+ dependent inactivation of SOCE. Moreover, reduced protein levels of Mfn2, a mitochondrial fusion protein, weaken the migration of STIM1 to SOCE channels, and ensuing SOCE activation in diabetic cells. Diabetic mouse hearts exhibit altered expression of MCU, which results in reduced mitochondrial Ca2+ uptake and subsequent attenuated SOCE activity. O denotes O‐GlcNAcylation