STIM1 in Regulation of Cardiac Energy Substrate Preference: History
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Contributor:
Panpan Liu
,
Zhuli Yang
,
Youjun Wang
,
Aomin Sun

The heart requires a variety of energy substrates to maintain proper contractile function. Glucose and long-chain fatty acids (FA) are the major cardiac metabolic substrates under physiological conditions. Upon stress, a shift of cardiac substrate preference toward either glucose or FA is associated with cardiac diseases. For example, in pressure-overloaded hypertrophic hearts, there is a long-lasting substrate shift toward glucose, while in hearts with diabetic cardiomyopathy, the fuel is switched toward FA. Stromal interaction molecule 1 (STIM1), a well-established calcium (Ca2+) sensor of endoplasmic reticulum (ER) Ca2+ store, is increasingly recognized as a critical player in mediating both cardiac hypertrophy and diabetic cardiomyopathy. However, the cause–effect relationship between STIM1 and glucose/FA metabolism and the possible mechanisms by which STIM1 is involved in these cardiac metabolic diseases are poorly understood.

  • STIM1
  • cardiac energy metabolism
  • cardiac hypertrophy
  • diabetic cardiomyopathy
  • glucose
  • fatty acid

1. Introduction

To maintain an optimal contractile function, the heart has a high demand for energy substrates to continuously form energy-rich phosphate bonds (i.e., intracellular adenosine triphosphate, ATP) [1]. Multiple substrates can be utilized by the heart to produce the necessary ATP, including glucose, lactate, long-chain fatty acids (FA), amino acids and ketone bodies, among which glucose and FA are the major metabolic substrates to generate acetyl-CoA for the tricarboxylic acid cycle and subsequent mitochondrial oxidation in healthy heart [2]. There is a balance between glucose and FA utilization in a healthy heart: FA contributes 60% of the ATP production via β-oxidation, while glucose provides 30% through glycolysis and glucose oxidation [3] (Figure 1). The remaining 10% of ATP is produced by lactate with minor contributions from ketone bodies and amino acids, which will not be addressed herein. However, this kind of balanced utilization of substrates can be changed toward a preference of either glucose or FA upon different pathological conditions (e.g., cardiac hypertrophy and diabetic cardiomyopathy), which causes gluco/lipo-toxicity and eventually cardiac dysfunction [4][5][6][7] (Figure 1).
In [8], researchers first discussed STIM1-dependent signaling in cardiomyocytes and metabolic changes in cardiac hypertrophy and diabetic cardiomyopathy. The researchers then provided examples of the involvement of STIM1 in energy metabolism to discuss the emerging role of STIM1 in the regulation of energy substrate preference in metabolic cardiac diseases and speculated the corresponding underlying molecular mechanisms of the crosstalk between STIM1 and cardiac energy substrate preference. Taken together, STIM1 emerges as a key player in regulating cardiac energy substrate preference, and revealing the underlying molecular mechanisms by which STIM1 mediates cardiac energy metabolism could be helpful to find novel targets to prevent or treat cardiac metabolic diseases.
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Figure 1. Diagram of the relation between the relative contributions of fatty acids and glucose to overall myocardial ATP production, contractile function and STIM1 expression. Contributions from lactate, ketone bodies, and amino acids are not shown here. In a healthy heart, there is a balance between fatty acids utilization and glucose utilization to produce ATP. However, when cardiac metabolic diseases like cardiac hypertrophy and diabetic cardiomyopathy occur, this balance shifts toward the predominant utilization of a single substrate, either fatty acids or glucose. This altered substrate preference is associated with changes in STIM1 expression.

2. STIM1-Dependent Signaling

STIM1 is a single transmembrane protein resident in ER/SR. It consists of a signal peptide (SP), the EF-hand and sterile alpha motif (EF-SAM) domain in the N-terminus (in the lumen of ER/SR), coiled-coil regions, an inhibitory domain (ID) and a polybasic region (K) in the C-terminus (in cytosol) (Figure 2a). The EF-SAM domain is responsible for its Ca2+-sensing role. There are three coiled-coil regions: coiled coil 1, 2, and 3 (CC1, 2, 3). CC1 has an inhibitory effect on CC2–CC3, which is the minimum domain of STIM1 to activate Orai1 (STIM1-Orai1 activating region, SOAR) [9][10][11][12] (Figure 2a). Under the resting state, Ca2+ binds to the EF-SAM domain to keep this ER-luminal region monomeric; CC1 interacts with SOAR to maintain cytosolic STIM1 domains in an auto-inhibitory dimeric folding form [11][13][14][15]. When the ER/SR Ca2+ store is depleted, the decalcified EF-SAM domains dimerize to pull the TM domains closer, triggering CC1 to release SOAR and unfold the cytosolic region of STIM1, promoting its oligomerization and the activation of Orai1, allowing Ca2+ influxes, or SOCE [11][16] (Figure 3).
Figure 2. Schematic presentation of (a) domains of STIM1 and its alternative splicing variants and (b) the localization of STIM1 in cardiomyocytes. (a) Cartoon of domains of STIM1 and alternative splicing variants. STIM1 is composed of the ER luminal domains that contain signal peptide (SP), the EF hand and SAM domain, transmembrane (TM) domain and the cytosolic domains that contain CC1, CC2, and CC3, the inhibitory domain (ID) and polybasic domains (K). The EF-SAM domain is able to bind Ca2+. CC2 and CC3 domains form the minimum domain of STIM1 to activate Orai1 (STIM1-Orai1 activating region, SOAR). Compared to STIM1, STIM1L has an extra actin-binding domain (ABD) of 106 amino acids. STIM1A/β has an extra 31 amino acids (A) after ID. STIM1B lacks 170 amino acids in the cytoplasmic domain but has an additional domain of 26 amino acids (B). (b) Cartoon illustration of the localization of STIM1 in cardiomyocytes. STIM1 and Orai1 are resident in SR at the Z-lines and sarcolemma, respectively. Close to STIM1 and Orai1, other key proteins involved in Ca2+ handling include the ryanodine receptor 2 (RyR2), voltage-gated Ca2+ channel Cav2.1, SR Ca2+ ATPase (SERCA) and inositol-1,4,5-triphosphate receptor (IP3R).
Figure 3. Cartoon illustration of activation and function of STIM1. STIM1 is a single transmembrane protein resident in ER/SR. Orai1 channel functions as a hexamer on plasma membrane. Under the resting state, the cytosolic region of STIM1 maintains an inactive folding configuration. Upon SR Ca2+ store depletion, the loss of Ca2+ triggers the dimerization of the STIM1 EF-SAM domain in the ER lumen, leading to the uncaging of its SOAR domain in the cytosol. SOAR would then bind and open Orai1, the pore-forming protein, inducing store-operated Ca2+ entry (SOCE). In addition to its critical roles in mediating many Ca2+-dependent signaling pathways, SOCE is also crucial for the maintenance of Ca2+ homeostasis within the ER/SR and mitochondria. Proper-sized ER Ca2+ store is essential for correct protein folding and processing as well as for maintaining Ca2+-dependent mitochondrial changes of the cell.
There are at least three known alternative splicing variants of STIM1 (STIM1L, STIM1A/β, and STIM1B) (Figure 2a). STIM1A/β has an insertion of 31-amino-acid peptide after the SOAR in the cytoplasmic domain, which is found in astrocytes, heart, kidney, and testes [17]. While STIM1A/β has been shown to more efficiently mediate SOCE with faster kinetics by disordering the cytosolic inhibitory domain in HEK, HeLa and glioblastoma cells [18], it was also shown to reduce SOCE in astrocytes in heterologous expression while at the same time increasing NFAT translocation due to a more efficient recruitment of the NFAT signalosome [17]. Indeed, it is possible that differential NFAT activation and not small differences in SOCE mediate a splice variant-specific effect in cells or else that the functions of STIM1A/β may differ in different cell types. STIM1B is a short isoform of STIM1, which lacks 170 amino acids but has an extra peptide of 26 amino acids in the cytoplasmic domain. STIM1B is a neuron-specific variant and induces slower ICRAC and the inactivation of ICRAC [19]. The C-terminal end of STIM1L bears an extra 106-amino-acids-long peptide that contains an actin-binding domain (ABD); thus, it can facilitate rapid SOCE [20][21]. STIM1L is only expressed in skeletal muscle cells, neonatal cardiomyocytes or hypertrophic adult cardiomyocytes [22].
In non-excitable cells, STIM1 is distributed throughout the ER at rest. Upon store depletion, STIM1 translocates to ER–PM junctions to interact and activate Orai1 to induce SOCE [9] (Figure 3). In cardiomyocytes, STIM1 is mostly localized in the SR at the Z-lines and is believed to function as a sensor for SR store [23][24][25][26]; the underlying mechanisms for this uneven distribution still awaits further investigation. Orai1 is detected in the sarcolemma membranes (Figure 2b). Around the area where STIM1 and Orai1 are resident is the well-known diad, which is a key place for excitation–contraction coupling (ECC) mediated by ryanodine receptor 2 (RyR2) at the terminal cisternae of the SR and voltage-gated Ca2+ channel Cav2.1 at the T-tubule (Figure 2b). Additionally, SR Ca2+ ATPase (SERCA) and inositol-1,4,5-triphosphate receptor (IP3R) are also involved in Ca2+ handling in this area (Figure 2b) [27]. Different from non-excitable cells, STIM1 forms constitutive puncta near sarcolemma and does not change its distribution upon store depletion [28]. In addition, there is barely co-localization between STIM1 and Orai1 in cardiomyocytes [28], indicating fewer involvements of Orai1 in STIM1-mediated SOCE. Indeed, STIM1 can hardly induce classic SOCE with Orai1, which is characterized by highly calcium-selective ICRAC with large inward rectification and very positive reversal potential [28][29]. Instead, a non-selective current is more commonly induced by STIM1 likely via the activation of transient receptor potential channels such as TRPC [29][30][31]. However, it is still controversial whether TRPC channels can be directly activated by STIM1 [32]. And Orai2 and Orai3 are both expressed in cardiac cells [33], thus it is also likely that STIM1 might mediate SOCE via interactions with Orai2 or Orai3.
STIM1-mediated SOCE is crucial for refilling ER Ca2+ [9][34][35] (Figure 3), as STIM1 deletion blocked the fast refilling of ER Ca2+ after store depletion [36][37]. Also, a decrease in STIM1 expression impaired ER Ca2+ refilling, which could be restored by STIM1 overexpression [38]. Similarly, it is believed that one key function of STIM1-mediated SOCE in cardiomyocytes is to refill SR Ca2+ and thereby maintain SR Ca2+ homeostasis for proper protein folding and processing [39]. STIM1 knockdown by siRNA in cultured neonatal rat ventricular cardiomyocytes reduced the SR Ca2+ content [23]. In addition, it has been shown that STIM1 overexpression increased the SR Ca2+ level in rat ventricular myocytes [30]. However, a study from Correll and colleagues showed that STIM1 overexpression had no effect on the total SR Ca2+ load in mouse ventricular myocytes. They suggested that elevated STIM1 resulted in increased Ca2+ uptake into the SR but also RyR2-dependent Ca2+ leak; therefore, the total SR Ca2+ load remained unaltered [25]. Ca2+ influx through STIM1-mediated SOCE refills ER/SR Ca2+ by SERCA. SERCA pumps have been shown to co-localize with STIM1 in different cell types, coupling Ca2+ entry with Ca2+ refilling [35]. In cardiomyocytes, SERCA is mainly resident at Z-lines where STIM1 is localized [40] (Figure 2b), likely enabling the similar function of Ca2+ entry–Ca2+ refilling coupling. A disruption of ER Ca2+ homeostasis can cause ER stress, leading to the accumulation of unfolded proteins and thus unfolded protein response (UPR) [41]. STIM1-knockout hearts displayed increased levels of ER stress marker CHOP [39]. Single-nucleotide polymorphisms (SNPs) in the STIM1 gene are correlated with ER stress in patients undergoing cardiac catheterization and spontaneous hypertension in rats [42][43]. Since ER stress and UPR often correlate with metabolic disorders [44][45][46][47][48], it is likely that STIM1 may mediate an energy substrate preference in cardiac metabolic diseases through regulating ER Ca2+ homeostasis.
In addition to refilling SR Ca2+, STIM1 could also activate downstream Ca2+-dependent metabolic pathways (Figure 3). It is widely accepted that Ca2+ signaling regulates cardiac energy metabolism through the direct activation of Ca2+-dependent proteins, kinases, enzymes and transcriptional regulators [49][50]. For instance, pyruvate dehydrogenase (PDH), PDH kinase (PDK), AMP-activated protein kinase (AMPK) and AKT are involved in the regulation of cardiac energy metabolism and are mediated by Ca2+ [51][52][53]. In addition, Ca2+ signaling regulates glycolysis and glucose oxidation in the heart and is crucial for the translocation of glucose transporter (GLUT) 4 and FA transporter CD36 (also known as the scavenger receptor B2, SR-B2) to the sarcolemma to induce cardiac glucose and FA uptake, respectively [54][55]. Moreover, peroxisome proliferator-activated receptor (PPAR) and PPARγ coactivator-1α (PGC-1α), key transcriptional regulators of expression of genes encoding mitochondrial oxidation enzymes, are associated with Ca2+ signaling as well [56][57]. Considering the key role of STIM1 in SOCE, STIM1 may regulate the energy substrate preference in cardiac metabolic diseases through Ca2+ signaling. Moreover, STIM1 can directly interact with a variety of other proteins [30][36][58][59][60][61][62][63][64], and alternative splicing variants of STIM1 might have splice-specific partners [17]. Interestingly, a recent report has shown that STIM1 negatively regulates the activation of stimulator of interferon genes (STING) through tethering STING to ER [65]. Of note, the cyclic GMP–AMP synthase (gGAS)–STING signaling pathway mediates cardiac metabolic abnormalities [66]. Therefore, STIM1 may regulate the energy substrate preference in cardiac metabolic diseases through the gGAS–STING signaling pathway or similarly via direct interactions with some other proteins correlating to energy metabolism. Given that glycolytic enzymes are clustered near SR [67] where STIM1 is resident, the likelihood of the conjecture increases.
Moreover, STIM1-mediated SOCE could contribute to cardiac metabolic diseases via the alteration of mitochondrial Ca2+ homeostasis or fission. Mitochondrial function including ATP production and reactive oxygen species (ROS) generation is regulated by Ca2+ [68][69]. Mitochondria takes up Ca2+ via voltage-dependent anion channel (VDAC) and mitochondrial Ca2+ uniporter (MCU) [70][71][72][73]. Normally, the ER/SR transmits Ca2+ to mitochondria to regulate mitochondrial function [74]. Therefore, STIM1-mediated SOCE is related to mitochondrial function through involvement in mitochondrial Ca2+ uptake from the ER/SR [25][75][76][77][78] (Figure 3). Alterations of ER/SR Ca2+ homeostasis due to the changes of STIM1-mediated SOCE would affect ER/SR–mitochondrial Ca2+ communication and thereby cause mitochondrial dysfunction. Excessive or insufficient mitochondrial Ca2+ in cardiomyocytes leads to mitochondrial dysfunction [79], which is associated with cardiac metabolic diseases such as cardiac hypertrophy and diabetic cardiomyopathy [79][80][81][82]. Interestingly, research has shown a decrease in mitochondrial Ca2+ uptake in diabetic hearts and restoring mitochondrial Ca2+ rescued mitochondrial and cardiac dysfunction [83]. In addition, Ca2+–calcineurin is involved in the regulation of mitochondrial fission, which is associated with the development of both cardiac hypertrophy and diabetic cardiomyopathy [78][84][85][86][87][88][89][90]. A recent study showed that STIM1 deficiency in cardiomyocytes changed mitochondrial morphology, which is indicative of an elevation of mitochondrial fission [39][91]. This phenomenon is in line with the fact that pro-fusion proteins (optic atrophy 1, Opa1; mitofusion 2, Mfn2) are downregulated, and the pro-fission protein (dynamin-related protein 1, Drp1) is activated, promoting mitochondrial fission in diabetic cardiomyocytes [78][88][89][90]. Notably, Mfn2 positively regulates SOCE via mediating STIM1 movement to ER–PM junctions [92], indicating there is a feedback loop between mitochondrial dynamics and STIM1-mediated SOCE. Therefore, any increase or decrease in STIM1 could induce mitochondrial dysfunction via influencing the mitochondrial Ca2+ level and mitochondrial fission, resulting in the alterations in cardiac glucose and FA oxidation. In turn, increased ROS due to mitochondrial dysfunction could downregulate STIM1 expression through NF-kB as a feedback effect [93]. Moreover, a study of T cells has shown that STIM1 deletion resulted in the downregulated expression of many subunits of the electron transport chain (ETC), suggesting that STIM1 is involved in mitochondrial function by controlling the expression of subunits of the ETC [94]. It would be intriguing to test this also the case in cardiomyocytes.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241713188

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