Open Access

Role of mitochondrial dysfunction and dysregulation of Ca2+ homeostasis in the pathophysiology of insulin resistance and type 2 diabetes

Journal of Biomedical Science201724:70

https://doi.org/10.1186/s12929-017-0375-3

Received: 19 April 2017

Accepted: 29 August 2017

Published: 7 September 2017

Abstract

Metabolic diseases such as obesity, type 2 diabetes (T2D) and insulin resistance have attracted great attention from biomedical researchers and clinicians because of the astonishing increase in its prevalence. Decrease in the capacity of oxidative metabolism and mitochondrial dysfunction are a major contributor to the development of these metabolic disorders. Recent studies indicate that alteration of intracellular Ca2+ levels and downstream Ca2+-dependent signaling pathways appear to modulate gene transcription and the activities of many enzymes involved in cellular metabolism. Ca2+ uptake into mitochondria modulates a number of Ca2+-dependent proteins and enzymes participating in fatty acids metabolism, tricarboxylic acid cycle, oxidative phosphorylation and apoptosis in response to physiological and pathophysiological conditions. Mitochondrial calcium uniporter (MCU) complex has been identified as a major channel located on the inner membrane to regulate Ca2+ transport into mitochondria. Recent studies of MCU complex have increased our understanding of the modulation of mitochondrial function and retrograde signaling to the nucleus via regulation of the mitochondrial Ca2+ level. Mitochondria couple cellular metabolic state by regulating not only their own Ca2+ levels, but also influence the entire network of cellular Ca2+ signaling. The mitochondria-associated ER membranes (MAMs), which are specialized structures between ER and mitochondria, are responsible for efficient communication between these organelles. Defects in the function or structure of MAMs have been observed in affected tissue cells in metabolic disease or neurodegenerative disorders. We demonstrated that dysregulation of intracellular Ca2+ homeostasis due to mitochondrial dysfunction or defects in the function of MAMs are involved in the pathogenesis of insulin insensitivity and T2D. These observations suggest that mitochondrial dysfunction and disturbance of Ca2+ homeostasis warrant further studies to assist the development of therapeutics for prevention and medication of insulin resistance and T2D.

Keywords

Ca2+ homeostasis Insulin resistance Metabolic disease Mitochondrial calcium uniporter Mitochondria-associated ER membranes Type 2 diabetes

Background

Regulation of Ca2+ homeostasis in metabolism

Ca2+ ions are involved in a number of signaling pathways to regulate metabolism, differentiation, proliferation, and life and death of the human cell. Intracellular Ca2+ levels should be tightly controlled in response to the timely demands of target cells. This regulation relies on an array of Ca2+ channels, transporters and exchangers located on the plasma membrane, the ER and mitochondrial membranes [1].

It has been proven that dysregulation of Ca2+ homeostasis is related to metabolic diseases such as obesity, insulin resistance and type 2 diabetes (T2D) in the human and animals. Higher intracellular Ca2+ level has been found in primary adipocytes isolated from obese human subjects with insulin resistance [2] and diabetic rats [3]. Besides, increase of serum Ca2+ level is positively correlated with the fasting blood glucose and insulin resistance index in the human [4]. Genome-wide association studies (GWASs) revealed that single nucleotide polymorphisms (SNPs) in sarco/ER Ca2+ ATPase (SERCA) [5] and inositol 1,4,5-trisphosphate receptors (IP3R) [6], which regulate intracellular Ca2+ homeostasis, are associated with the susceptibility to higher body mass index (BMI) and diabetes. Moreover, chelation of Ca2+ ions could improve insulin sensitivity of rats fed on the high-fat diet [7].

Many studies have shown that disturbance of Ca2+ homeostasis is a key factor in the dysregulation of metabolism. Intracellular Ca2+ fluctuation has been substantiated to play a role in the downstream signaling of insulin stimulation. The cytosolic Ca2+ level of adipocytes was found to increase upon insulin stimulation [8]. Inhibition of downstream Ca2+ signaling either by treatment of calmodulin (CaM) antagonists [8] in adipocytes or by knockdown of IP3R in the primary rat cardiomyocytes [9], respectively, could decrease Glut4 translocation and glucose uptake upon insulin stimulation. Inhibition of Ca2+ influx by 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of IP3R and TRP channels, ameliorated insulin-stimulated glucose uptake in skeletal muscle while there was no change in the phosphorylation of Akt [10]. Thus, an increase in the intracellular Ca2+ level and the activation of Ca2+ sensing proteins may directly or indirectly modulate Glut4 exocytosis, which is the most important step for glucose utilization of muscle cells in response to insulin.

The change in the distribution of some proteins has been demonstrated to play a role in Ca2+-mediated insulin action. Recent studies revealed that in adipocytes, synaptotagmin VII (Syt VII) can modulate the translocation of Glut4 and glucose utilization in response to insulin [11]. This finding indicates that Syt VII serves as a downstream sensor of Ca2+ signaling to regulate the insulin signaling pathway. Secondly, an actin-binding protein, Myo1c, has been shown to participate in the insulin-stimulated Glut4 translocation, which is regulated by Ca2+/CaM signaling because the effect was diminished by treatment with trifluoperazine, a CaM inhibitor [12, 13]. This notion was supported by the finding that phosphorylation of Myo1c by Ca2+/CaM kinase II (CaMKII) contributes to insulin-triggered regulation of Glut4 translocation in 3 T3-L1 pre-adipocytes [14]. Moreover, it was demonstrated that FAM3A can facilitate the activation of PI3K/Akt in insulin signaling in liver to improve insulin sensitivity and decrease hepatic gluconeogenesis to control blood glucose in mice [15]. Moreover, activation of Ca2+/CaM signaling is required for the FAM3A-mediated Akt activation [15]. In light of the above observations in different cell types and cellular conditions, it is imperative to explore specific Ca2+-dependent effectors or Ca2+/CaM signaling cascades in the regulation of insulin action under different conditions.

In addition to their role in the action of insulin, Ca2+ ions are also involved in adiponectin-mediated regulation of metabolism. Adiponectin has received increasing attention than other adipokines due to the observation that its level is negatively associated with metabolic syndrome and its beneficial effect on cellular bioenergetic metabolism in diabetic mouse models [16, 17]. Briefly, when adiponectin binds to its receptor, AdipoR, in muscle cells, it triggers an increase of Ca2+ flux into cytoplasm and activation of Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ). In turn, CaMKKβ could further stimulate AMPK activation to induce glucose uptake and β-oxidation of fatty acids. On the other hand, CaMK could also be activated by CaMKKβ, which transcriptionally regulates the expression of PGC-1α to increase the biogenesis and function of mitochondria in muscle cells [17, 18]. These findings suggest that Ca2+-dependent signaling cascade is involved in the action of adiponectin to improve not only glucose homeostasis but also lipid metabolism of muscle and other peripheral tissues.

Abundant evidence has substantiated that dysregulation of intracellular Ca2+ can cause defects in lipid metabolism in mammalian cells. Functional genetic screens in Drosophila demonstrated the importance of dSERCA and the ryanodine receptor (dRyR) [19], dIP3R [20], and dStim [21] in lipid homeostasis. Recently, abnormal accumulation of lipid droplets was observed in the liver, heart, and skeletal muscle of the SOCE-deficient mice [22]. Fibroblasts isolated from patients with loss-of-function mutations in the STIM1 or ORAI1 gene revealed defects in the mobilization of fatty acids from lipid droplets, lipolysis, and β-oxidation of fatty acids [22].

Mitochondria regulate intracellular Ca2+ homeostasis

Mitochondria are able to modulate influx and efflux of Ca2+ ions to alter both the amplitude and the spatio-temporal distribution pattern of the intracellular Ca2+ levels. The mitochondrial membrane potential produces a large electrochemical gradient (usually between −150 and −200 mV) of the inner membrane of mitochondria so that Ca2+ ions can freely cross the outer membrane of mitochondria (OMM). However, there are distinct systems to import or efflux Ca2+ through the inner membrane of mitochondria (IMM). Mitochondrial Ca2+ uniporter machinery facilitates the entry of Ca2+ ions to the matrix. H+/Ca2+ and Na+/Ca2+ exchangers (NCX) efflux Ca2+ ions from matrix to the cytosol. Tight regulation of these proteins is important to increase the Ca2+ level to activate mitochondrial enzymes and to prevent accumulation of Ca2+ ions and Ca2+ overload within the mitochondria [23].

The influx and efflux rates of Ca2+ between mitochondria must be balanced. Disruption of this balance may result in the opening of the mitochondrial permeability transition pore (mPTP) and the induction of cell death [24]. Ca2+ ions taken up into the mitochondrial matrix can increase ATP production via Ca2+-dependent activation of three important metabolic enzymes in the matrix, which include the pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase (αKGDH) and isocitrate dehydrogenase (IDH) [25]. The mitochondrial Ca2+ uptake will affect Ca2+ signaling at local and the global levels. The Ca2+ ions released through the activation of IP3 receptor of ER in response to external stimuli can activate a series of signal transductions, but these activations need to be shut down at the right moment by sequestration of Ca2+ ions into mitochondria. This regulation highly depends on the efficiency of the functional coupling between mitochondria and ER and on the subcellular distribution of mitochondria [26]. Thus, the buffering capacity of Ca2+ ions by mitochondria plays a crucial role in the modulation of the Ca2+-dependent signaling and in the pathophysiology of a wide spectrum of diseases [27, 28].

Mitochondrial calcium uniporter complex in human cells

Mitochondrial calcium uniporter complex, a highly selective channel responsible for Ca2+ uptake of mitochondria, consists of both pore-forming and regulatory subunits (Fig. 1). Human mitochondrial calcium uniporter (MCU) complex has been identified as a large protein complex (~480 kDa) in the intensive studies of past few years [29, 30]. MCU is composed of two coiled-coil domains and two transmembrane domains and is the main channel for Ca2+ uptake [31, 32]. The other two pore-forming proteins are MCUb [33] and essential MCU regulator (EMRE) [34]. It has been shown that MCU per se is sufficient to execute the Ca2+ uptake. MCUb shares a 50% similarity with the MCU but the difference of some amino acids in the pore forming region makes it an inhibitory subunit [33]. EMRE was just identified by SILAC-based quantitative mass spectrometry in 2013 by Sancak et al. [34]. Recently, EMRE has been demonstrated as a matrix Ca2+ sensor and its interaction with MICU1 contributes to collaborative regulation of the Ca2+ uptake current of the MCU complex. Deletion of its matrix-localized acidic C-terminal domain abolished the regulation, causing an increase of Ca2+ uptake from MCU [35].
Fig. 1

Mitochondrial calcium uniporter complex and the regulation of the entry of Ca2+ ions into mitochondria. The protein complex of mitochondrial calcium uniporter is composed of the pore-forming proteins (MCU, MCUb, EMRE), and the regulatory proteins (MICU1, MICU2). The regulation of the entry of Ca2+ ions by mitochondrial calcium uniporter complex is demonstrated here. a When the concentration of Ca2+ ions is low in the IMS, the heterodimer of MICU1 and MICU2 blocks the channel of MCU to inhibit the entry of Ca2+ ions. b When the Ca2+ ions level is high upon stimulation, binding of Ca2+ ions to the MICU protein elicits a conformational change to open the channel, resulting in the transport of Ca2+ ions into mitochondria to activate several dehydrogenases in the matrix of mitochondria. IMS, intermembrane space; IMM, inner mitochondrial membrane

Mitochondrial calcium uptake proteins (MICU) in the intermembrane space of mitochondria have been identified as regulatory proteins to control the Ca2+ ion transport through the MCU. There are three MICU proteins in human cells and all of them contain the EF hand domain for Ca2+ binding [36]. MICU1 and MICU2 are ubiquitously expressed in mammalian tissues, but MICU3 is restricted to the central nervous system [37]. MICU2 forms an obligate heterodimer with MICU1 through a disulfide bond that interacts with MCU. A model proposed for the regulation of Ca2+ uptake in human cells is described in Fig. 1. Briefly, when Ca2+ ion concentration in the intermembrane space of mitochondria is low, the heterodimer of MICU1 and MICU2 blocks the MCU channel to prevent uptake of Ca2+ ions by mitochondria. When there is an increased release of Ca2+ ions from ER or import from extracellular compartments, the elevation of cytosolic level of Ca2+ ions will increase the binding of Ca2+ ions to MICU proteins. Upon increase of cytosolic Ca2+ ions, the inhibition of MCU is relieved due to the conformational change of MICU1 and MICU2 after Ca2+ ion binding, and Ca2+ ions could then be transported through the MCU [38].

Dysregulation of mitochondrial Ca2+ ions in human diseases

One of the physiological roles of the MCU complex has been established in the control of ATP production through activation of Ca 2+-dependent dehydrogenases in the mitochondrial matrix, modulation of the duration of cytosolic Ca2+ signals by buffering cytosolic Ca2+ ions. The identification of the molecular components of the uniporter provides an unprecedented opportunity to unravel the role of mitochondrial Ca2+ ions in the regulation of cellular metabolism in more detail using genetic tools (Table 1).
Table 1

The role of mitochondrial Ca2+ homeostasis in cellular functions

Study subjects

Manipulation of mitochondrial Ca2+ ions

Observations

Ref.

 In vitro

  Human

   HeLa cells

knockdown of MCU

increase of mitochondrial Ca2+

[40]

increase of ROS

[40]

decrease of SOCE response

[43]

   Lung cells

knockdown of MCU

decrease of inflammasome activation

[44]

decrease of ROS

[44]

   Skin fibroblasts

point mutation of MICU1

decrease of maximal OCR

[47]

increase of mitochondrial Ca2+ uptake

[47]

   HEK cells

C-terminal deletion of EMRE

increase of mitochondrial Ca2+

[35]

   Hepatocytes

knockdown of MAMs components (IP3R, VDAC, GRP75)

decrease of insulin signaling

[69]

 Rat

   

   Beta cells

knockdown of MCU or MICU1

decrease of mitochondrial Ca2+

[41]

decrease of glucose-stimulated insulin secretion

[41]

   Leukemia cells

knockdown of MCU

decrease of SOCE response

[42]

decrease of mitochondrial Ca2+ uptake

[42]

   Cardiomyocytes

overexpression of TFAM

increase of mitochondrial Ca2+

[61]

increase of ATP production

[61]

increase of SERCA expression

[61]

 Mouse

   Adipocytes

downregulation of TFAM, PGC-1α

decrease of mitochondrial Ca2+

[62]

increase of ROS

[62]

decrease of insulin-stimulated glucose uptake

[62]

 In vivo

  Mouse

   Skeletal muscle

knockout of MCU

decrease of mitochondrial Ca2+ uptake

[39]

decrease of maximal OCR

[39]

decrease of PDH activity

[39, 46]

decrease of muscle function

[39]

decrease of muscle size

[46]

defects in mitochondrial morphology

[46]

   Heart

overexpression of DN-MCU

decrease of maximal OCR

[45]

decrease of heart rate upon stimulation

[45]

   Adipose tissue

knockdown of MAMs components (Cisd2)

glucose intolerance

[60]

decrease of maximal OCR

[60]

decrease of mitochondrial Ca2+ uptake

[60]

   Liver

knockout of MICU1

increase of mitochondrial Ca2+

[48]

increase of ROS

[48]

decrease of ATP

[48]

defects in mitochondrial morphology

[48]

knockdown of MICU1

impaired liver regeneration

[49]

inflexibility of MAM structure

decrease of maximal OCR

[72]

decrease of glucose infusion rate

[72]

glucose intolerance

[72]

knockdown of MAMs components (CypD)

hepatic insulin resistance

[69]

It is accepted that MCU plays a role in excitation-energetic coupling through the activation of mitochondrial matrix dehydrogenases. Manipulation of components in the MCU complex could alter the activity of the PDH complex and intracellular ATP levels of human cells. Ca2+-sensitive PDH phosphatase (PDP) activated by Ca2+ ions in the matrix can dephosphorylate PDH and increase its activity. The MCU complex activity is positively correlated with the PDH activity and oxidative phosphorylation in mitochondria. A deficiency of MCU in skeletal muscle resulted in an increase of phosphorylation of PDH and concomitant decrease of PDH activity [39]. Knockdown of MICU1, which led to an increase of basal levels of Ca2+ ions in the mitochondrial matrix, decreased the phosphorylation and increased the activity of PDH in HeLa cells [40]. Furthermore, ablation of MCU in pancreatic β cells exhibited a decrease of intracellular ATP concentration following glucose stimulation [41]. This resulted in diminished glucose-stimulated insulin secretion [41]. Thus, the above-mentioned in vitro studies have provided compelling evidence to substantiate that MCU plays a role in excitation–energetic coupling.

It has been shown that alteration of the MCU complex is involved in regulating transient fluxes of cytosolic Ca2+ ions to modulate the cellular metabolism. It was demonstrated that Ca2+ signaling downstream of the leukotriene receptor is influenced by MCU [42]. In rat basophils, knockdown of MCU resulted not only in defective mitochondrial Ca2+ uptake but also in the suppression of Ca2+-dependent gene expression following stimulation of the leukotriene receptor with leukotriene C4 (LTC4). The MCU seems to involve in two processes that are relevant to the immune signaling: store-operated calcium entry (SOCE) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Lack of MCU has been shown to reduce the SOCE response after inositol trisphosphate-mediated Ca2+ ions release from ER [43], which is the underlying cause of defects in the activation of the NLRP3 inflammasome induced by Pseudomonas aeruginosa in airway epithelial cells from patients with cystic fibrosis [44]. Taken together, these different lines of evidence confirm a role for the MCU uniporter in cellular Ca2+ signaling and substantiate its importance in the immune response.

MCU deficiency can be tolerated in mice with a mixed genetic background. MCU knockout was found to be lethal in C57BL/6 mice, whereas the knockout mice with an outbred CD1 background were viable. MCU-knockout CD1 mice displayed no obvious phenotype but exhibited impaired tolerance to exercise. This is consistent with a cellular role of MCU in stimulating the activity of the TCA cycle during Ca2+ signaling events associated with muscle contraction [39]. In addition to whole-body MCU knockout, the overexpression of a dominant-negative MCU protein in sinoatrial node cells in mice also revealed a link between the Ca2+ uniporter activity and cellular energetics [45]. Although there was no significant difference at base line between wild-type and mutant animals, the heart rate was unable to increase in mutant mice in response to β adrenergic agonists. This observation revealed an important role of the MCU complex in the ‘fight-or-flight’ response of the animals. Skeletal muscle cells infected with adeno-associated viral vectors (AAVs) was used to create the overexpression or knockdown of MCU in the tissue specific manner. Overexpression of MCU triggered skeletal muscle hypertrophy during post-natal development and knockdown of MCU led to muscle atrophy in adulthood [46]. Notably, MCU overexpression could protect muscle tissues from the loss of muscle mass upon denervation, indicating a potential therapeutic role of MCU modulation in muscle atrophy [46]. Taken together, these findings demonstrate the physiological importance of MCU as the major mammalian Ca2+ uniporter, including its role in skeletal muscle contraction and in the response of cardiac muscle to adrenergic stimulation.

Loss of MICU1 expression by truncating mutations in the human could lead to skeletal muscle myopathy, learning disability and movement disorder [47]. The pathological phenotypes caused by the loss of MICU1 manifests in a tissue-specific manner, which is reminiscent of mitochondrial disorders. Deficiency of the MICU1 could result in an increase of perinatal mortality in mice [48, 49]. The surviving mice showed ataxia and muscle weakness which is similar to afflicted patients. MICU1 KO led to Ca2+ overload in mitochondria and increase of ROS production. Interestingly, the impairment of Ca2+ regulation could be restored by age-dependent decline of the EMRE expression. This indicates that the remodeling of MCU complex may help to maintain the Ca2+ homeostasis [48]. Hepatocyte-specific MICU1 knockdown by the injection of AAV-Cre did not reveal significant gross defect in liver but the liver was unable to regenerate from injury. In addition, MICU1-deficienct hepatocytes were found to be more susceptible to the opening of mitochondrial permeability transition pores (mPTP) [49]. Future studies are warranted to answer the questions as to whether patients with mutations in MICU1 have pathological involvement of other organ systems, especially in tissues with high energy-demand or high mitochondrial content like brain, liver, and brown adipose tissue.

Mitochondria-nuclear crosstalk via Ca2+ signaling

The retrograde signals from mitochondria can trigger gene transcription in the nucleus to induce adaptive responses or modulate cellular metabolism [50]. Although the reactive oxygen species (ROS) production in mitochondrial respiration has been known as putative retrograde signaling molecules linking mitochondrial dysfunction to insulin insensitivity [51], the emerging evidence has substantiated the importance of other known mitochondrial retrograde signals. Recent studies have pointed out the crucial role of Ca2+ signaling from mitochondria in the regulation of cell metabolism. Dysregulation of intracellular Ca2+ homeostasis due to ATP depletion and release of Ca2+ ions from the mitochondria have been proposed as a principal cause for insulin resistance, but no detailed studies have been performed yet on the mitochondrial and cellular Ca2+ transport processes to clarify this issue. Although it is established that transcriptional control of metabolism by Ca2+ is exerted indirectly via Ca2+-dependent kinases and phosphatases, such as CaMK and calcineurin, which regulate the expression of PGC-1α [52], the underlying mechanism that generates the retrograde signals remains to be determined. It is important to answer the questions as to whether the feedback regulation between mitochondria and the nucleus is effected through the cellular and mitochondrial Ca2+ signaling networks and what are the components involved in these processes.

Many studies have revealed that an increase in the intracellular Ca2+ level can inhibit the differentiation and maturation of human mesenchymal stem cells and 3 T3-L1 preadipocytes. For example, increases of the intracellular Ca2+ level by incubation of adipocytes in the culture media containing a high concentration of Ca2+ ions [53], activation of Ca2+ ion channels or receptors [54, 55], and inhibition of SERCA by thapsigargin [56] have been demonstrated to interrupt the adipogenic differentiation signaling in 3 T3-L1 preadipocytes. Ca2+-dependent enzymes including calcineurin (CaN), a Ca2+-dependent phosphatase, CaMKII, a Ca2+/CaM kinase 2 as well as calreticulin (Calr), a Ca2+-buffering chaperone in the ER, have been demonstrated, respectively, to play important roles in adipogenesis [5759]. In a very recent study, we showed that mitochondrial dysfunction induced by Cisd2 deficiency increased the cytosolic level of Ca2+ ions and activated Ca2+-calcineurin-dependent signaling, which inhibited the transcriptional cascades at the late stage of adipogenesis in mice [60]. These findings indicate that the maintenance of Ca2+ homeostasis and normal mitochondrial function by Cisd2 are essential for adipogenic differentiation and function of adipocytes, which in turn regulates systemic glucose homeostasis in mice. Dysregulation of Ca2+ homeostasis and insulin insensitivity could be similarly induced in mouse progenitor cells-derived adipocytes with genetic manipulation of TFAM [61] or down-regulation of PGC-1α expression [62]. These genetic approaches have provided different lines of evidence to support the notion that disturbance of Ca2+ homeostasis caused by mitochondrial dysfunction plays an important role in T2D and insulin resistance in mice. Regulation of mitochondrial Ca2+ ions also modulates the morphology of the skeletal muscle. MCU overexpression by adeno-associated viral vectors induced muscle hypertrophy and MCU silencing triggered muscle hypotrophy in mice [46]. The control of muscle size involves the regulation of the expression of a set of genes by IGF-AKT and PGC-1α signaling cascades [46]. In addition, RNA microarray analyses demonstrated that modulation of the activity of MCU could control the global gene expression, thereby led to the identification of a Ca2+-dependent mitochondria-to-nucleus route that links mitochondrial function to the control of muscle mass [63].

Mitochondria-associated ER membranes (MAMs)

Mitochondria-associated ER membranes (MAMs) are the contact sites between the mitochondrial outer membrane and ER membrane, which are defined as structural membranes between the two organelles [26]. This special intracellular membrane structure is crucial for an accurate and efficient communication and transport of Ca2+ ions between the two organelles, which are the two largest Ca2+ storage sites in human cells. MAMs are responsible for dynamic and efficient transmission of physiological and pathological Ca2+ signals between the ER and the mitochondria. Due to the enrichment of Ca2+ handling proteins present in the MAMs, the functional coupling at the ER-mitochondria interface is very important for the regulation of intracellular Ca2+ homeostasis during metabolic reprogramming and cellular adaptation to various physiological and environmental stimuli [64]. In addition, it has been suggested that MAMs serve as an integrator of energy metabolism because of the enrichment in MAMs of functionally diverse enzymes involved in the metabolism of glucose and fatty acids [65, 66].

Alterations of ER-mitochondria coupling contributes to insulin resistance in obesity and diabetes

Defects in MAMs have been suggested to play a role in the pathogenesis of diseases such as Alzheimer’s disease, insulin resistance and T2D [64, 67, 68]. An in situ proximity ligation assay (PLA) was developed to visualize and quantify the ER-mitochondria connections by monitoring the interactions between VDAC1-IP3R1, Grp75-IP3R1 and CypD-IP3R1, respectively. Using this technique, the disruption of MAMs integrity could be observed in primary hepatocytes from the obese mice or palmitate-induced insulin resistance in the mouse or cultured cells [69]. Knockdown of IP3R1 to reduce MAMs structure could trigger mitochondrial dysfunction and glucose intolerance in obese mice. In addition, it was found that diabetic mice treated with rosiglitazone or metaformin not only reinforce MAMs integrity but also improve insulin sensitivity and glucose homeostasis [69]. Restoration of MAMs by overexpression of Grp75 could also improve insulin sensitivity in palmitate-treated primary culture of hepatocytes [69]. Primary cultures of hepatocytes and HuH7 cell line recapitulated the phenotype of insulin resistance in media containing high concentrations of glucose, which was associated with the decrease of interactions in MAMs, mitochondrial fragmentation, decrease of the dynamics and respiration rate of mitochondria [70]. Mechanistically, hepatocytes cultured in media containing high concentration of glucose exhibited an increase of flux through pentose phosphate pathway and activation of protein phosphatase 2A (PP2A) [70]. On the other hand, high glucose also decreased the transport of Ca2+ ions to mitochondria and increase of cytosolic level of Ca2+ ions, which could further activate PP2A. Thus, inhibition of PP2A by okadaic acid could prevent high glucose-induced disruption of MAMs and restored the morphology and bioenergetic function of mitochondria [70]. Impairment of ER-mitochondria interactions and abnormality of Ca2+ homeostasis have also been observed in the liver of mice with deficiency of cyclophilin D (CypD), which is a mitochondrial protein that regulates mPTP and was recently found in MAMs fractions. Conversely, restoration of MAMs integrity by overexpression of CypD could improve insulin sensitivity and insulin signaling cascade [71]. In contrast, abnormal chronic increases in the formation of MAMs resulted in mitochondrial Ca2+ ions overloading, which could impair the mitochondrial bioenergetic function and increase the ROS production in the liver of obese mice [72]. Although the discrepancy still exists as to whether increase or decrease of MAMs structure is better for the regulation of Ca2+ homeostasis, the common conclusion is that MAMs structure should be flexible and dynamic for an efficient control of the Ca2+ level in response to stimuli or the change of nutrients.

It has been reported that Cisd2 is localized on both ER and mitochondrial membranes [73, 74]. Cisd2 deficiency could lead to an alteration of Ca2+ ions level in the ER [74]. Recently, we provided evidence to show that direct interactions exist between Cisd2 and Gimap5 on the MAMs and thereby modulate the mitochondrial uptake of Ca2+ ions, which in turn regulate the intracellular Ca2+ homeostasis. This novel role of Cisd2 in MAMs is crucial for adipogenic differentiation and function of adipocytes, and even in the glucose tolerance and insulin sensitivity of the mouse [60]. Taken together, these observations suggest the importance of MAMs in the regulation of Ca2+ level and mitochondrial function, which may participate in the modulation of glucose homeostasis and insulin sensitivity. It is worth mentioning that MAMs formation is a dynamic process to support efficient transmission of Ca2+ ions and lipid biosynthesis, which culminates in an increase of mitochondrial function to meet the cellular energy demand under stress conditions. The fluctuating feature of MAMs in cooperation between ER and mitochondria provides an inter-organelle communication for tissue cells to adapt to specific physiological and environmental conditions.

Conclusion

This review has provided an overview of recent advances in the role of mitochondrial dysfunction and dysregulation of intracellular Ca2+ homeostasis in the pathogenesis of metabolic diseases such as insulin resistance and T2D (Fig. 2). We have especially focused on the dysregulation of intracellular Ca2+ homeostasis caused by functional defects in the MCU complex, which is located on the inner membrane of mitochondria. Although overproduction of ROS and defects in lipid metabolism have been established as a common cause of T2D and insulin resistance, the defects in the maintenance of intracellular Ca2+ levels by mitochondria deserves proper attention. In addition, mitochondrial Ca2+ has been well documented in the contribution of ROS production within mitochondria [75]. Given that mitochondria are intracellular organelles involved in the execution of many cellular functions and that there are multiple pathways involved in the regulation of metabolism, in-depth studies of the effects of mitochondrial dysfunction on Ca2+ homeostasis are warranted to gain a better understanding of the complex pathophysiology of metabolic disorders.
Fig. 2

Illustration of the role of defects in mitochondria-mediated regulation of Ca2+ homeostasis in the pathogenesis of insulin resistance and type 2 diabetes. The intracellular level of Ca2+ ions in a normal human cell is regulated and maintained within a small range of concentration. The fluctuation of the level of Ca2+ ions from extracellular influx or release of intra-organelle leads to activation of Ca2+-dependent signaling to alter the gene expression or protein trafficking in response to the stimulation (i.e., adiponectin or norepinephrine). Increase of cytosolic level of Ca2+ ions initiates the activation of insulin signaling and transcriptional regulation in insulin-responsive tissues such as adipocytes and muscle. On the other hand, Ca2+ ions can facilitate insulin secretion in beta cells. All of these effects are beneficial to glucose utilization and insulin sensitivity in the human body. For instance, the Ca2+-dependent activation of FAM3A improves phosphorylation of AKT and the activation of CaMKII or synaptotagmin VII (Syt VII) allow efficient translocation/docking/fusion of glucose transporter 4 (Glut4) to the plasma membrane in insulin- responsive cells upon insulin stimulation. Moreover, Ca2+ homeostasis also regulates gene transcription to affect adipogenesis, muscle trophism, and mitochondrial biogenesis through Ca2+-dependent activation of a number of proteins. Mitochondria modulate intracellular Ca2+ homeostasis by its high capacity of Ca2+ uptake through the MCU complex and interaction with ER via the MAMs structure. Mitochondrial Ca2+ uptake plays as a role in the buffering of cytosolic Ca2+ ions and in the boost of the ATP production. Three enzymes (PDH, IDH, αKGDH) involved in oxidative metabolism are regulated by Ca2+ ions directly or indirectly, providing more NADH to the electron transport chain (ETC). Mitochondrial dysfunction disrupts intracellular Ca2+ homeostasis and leads to dysregulation of the above-mentioned Ca2+-dependent signaling events and impairment of glucose utilization and insulin response in the affected cells. Ultimately, these abnormalities will culminate in insulin insensitivity of target tissue cells and thereby develop T2D

After identification of the MCU complex, the key regulator of the mitochondrial Ca2+ signaling, a new area of research has emerged. Molecular genetic manipulation and development of transgenic animal models have allowed us to directly address exciting issues of mitochondrial Ca2+ signaling in the pathophysiology of diseases associated with mitochondrial dysfunction. In the past decade, we have witnessed the advances in a better understanding of the roles of Ca2+ transporters in the regulation of Ca2+ homeostasis, mitochondrial bioenergetics and even in metabolic reprogramming. However, many aspects of mitochondrial dysfunction in the pathogenesis of diseases await further investigation. Until now, the stoichiometry and oligomeric state of each of the components of the MCU complex, the major mitochondrial Ca2+ uniporter, and the dynamic change of their stoichiometry have remained unknown. Elucidation of the composition of the MCU complex in different cell types at distinct developmental stages is most important. The expression levels of specific component in the MCU complex have been determined in different tissues and cell lines. Some studies have shown that the relative expression levels of MCU and its interaction partner proteins are in line with the predicted mitochondrial Ca2+ uptake behavior. However, we do not exclude the possibilities that other regulatory systems may contribute to the regulation of the MCU activity. In addition, what kinds of signaling or stimuli that contribute to transcriptional regulation of genes in the MCU complex are still unclear. Interestingly, the alteration in the expression ratio between MCU and its negative-dominant MCUb in different types of tissues suggests that it might contribute to the spatiotemporal control of mitochondrial uptake of Ca2+ ions and Ca2+-dependent activation of mitochondrial function. Given that protein modification can rapidly regulate the function, interaction, and conformational change of proteins, work has to be done in the future on the post-transcriptional regulation of the function of the MCU complex, which certainly plays an important role in the cellular response to external stimuli and physiological signals.

Most importantly, we discuss in this review the importance of mitochondria-ER cross-talk in the maintenance of Ca2+ homeostasis and suggest that dysregulation of this inter-organelle communication may play a key role in the pathogenesis of insulin insensitivity and T2D. Lack of Cisd2, an iron-sulfur protein localized in the MAMs, significantly affects this inter-organelle communication and alters the Ca2+ buffering capacity of mitochondria in adipocytes. Moreover, recent studies demonstrated that ER-mitochondria interactions were decreased in diabetic mice and in primary culture of hepatocytes and in HuH7 cells that had been cultured in a high-glucose medium or treated with palmitate. These findings indicate that the structural integrity of MAMs may contribute to the maintenance of Ca2+ homeostasis. It is thus important to determine the dynamic properties of MAMs in different type of cells under different cellular context and physiological conditions. When addressing the communication between the two organelles, the reciprocal effects on Ca2+ homeostasis from each other should be considered. Further studies are warranted to elucidate the cross-talk and responses between defective mitochondria and ER. It is imperative to clarify whether there are concomitant beneficial effects for ER when adipocytes are treated with mitochondria-targeting antioxidants (such as mito-CoQ10). The insight gained from studies of the inter-organelle communications can help us better understand the pathogenesis of the complicated and multifactorial disorders such as T2D. This line of research will also provide us novel information for the development of therapeutic agents to improve the function and/or structural integrity of MAMs. We have demonstrated that dysregulation of Ca2+ homeostasis is a novel mechanism underlying the mitochondrial dysfunction-related insulin insensitivity of adipocytes and possibly an etiology factor of T2D. We believe that simultaneous improvement of the structure and function of mitochondria and ER may be a useful strategy to restore and maintain glucose homeostasis in the human and animals.

Abbreviations

2-APB: 

Aminoethoxydiphenyl borate

AAVs: 

Adeno-associated viral vectors

AdipoR: 

Adiponectin receptor

BMI: 

Body mass index

Calr: 

Calreticulin

CaM: 

Calmodulin

CaMKII: 

Ca2+/CaM-dependent protein kinase II

CaMKKβ: 

Ca2+/CaM-dependent protein kinase kinase β

CaN: 

Calcineurin

EMRE: 

Essential MCU regulator

GWASs: 

Genome-wide association studies

IDH: 

Isocitrate dehydrogenase

IMM: 

Inner mitochondrial membrane

IP3R: 

Inositol 1,4,5-trisphosphate receptors

LTC4: 

Leukotriene C4

MAMs: 

Mitochondria-associated ER membranes

MCU: 

Mitochondrial calcium uniporter

MICU: 

Mitochondrial calcium uptake proteins

mPTP: 

Mitochondrial permeability transition pore

NCX: 

Na+/Ca2+ exchangers

NLRP3: 

NLR family pyrin domain containing 3

OMM: 

Outer mitochondrial membrane

PDH: 

Pyruvate dehydrogenase

PDP: 

PDH phosphatase

ROS: 

Reactive oxygen species

RyR: 

Ryanodine receptor

SERCA: 

Sarco/ER Ca2+ ATPase

SNPs: 

Polymorphisms

SOCE: 

Store-operated calcium entry

Syt VII: 

Synaptotagmin VII

T2D: 

Type 2 diabetes

TCA cycle: 

Tricarboxylic acid cycle

αKGDH: 

α-ketoglutarate dehydrogenase

Declarations

Acknowledgements

We would like to acknowledge partial financial support from the intramural research fund of Changhua Christian Hospital and Mackay Medical College.

Funding

This review has been prepared on the basis of research work supported by research grants (MOST 104-2320-B-715-MY2, MOST 105-2627-M-715-001 and MOST 106-2627-M-371-001) from the Ministry of Science and Technology, Executive Yuan, Taiwan.

Availability of data and materials

Not applicable.

Authors’ contributions

CH Wang collected references and prepared the first draft of the manuscript and organized the figures and Table. YH Wei conceived the idea and outlined the review and revised the manuscript and suggested modifications for the figures and the table.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital
(2)
Institute of Biochemistry and Molecular Biology, National Yang-Ming University
(3)
Institute of Biomedical Sciences, Mackay Medical College

References

  1. Berridge MJ. Calcium signalling remodelling and disease. Biochem Soc Trans. 2012;40(2):297–309.View ArticlePubMedGoogle Scholar
  2. Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988;82(6):1848–52.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Draznin B, Lewis D, Houlder N, Sherman N, Adamo M, Garvey WT, LeRoith D, Sussman K. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology. 1989;125(5):2341–9.View ArticlePubMedGoogle Scholar
  4. Yamaguchi T, Kanazawa I, Takaoka S, Sugimoto T. Serum calcium is positively correlated with fasting plasma glucose and insulin resistance, independent of parathyroid hormone, in male patients with type 2 diabetes mellitus. Metabolism. 2011;60(9):1334–9.View ArticlePubMedGoogle Scholar
  5. Varadi A, Lebel L, Hashim Y, Mehta Z, Ashcroft SJ, Turner R. Sequence variants of the sarco (endo) plasmic reticulum Ca2+-transport ATPase 3 gene (SERCA3) in Caucasian type II diabetic patients (UK prospective diabetes study 48). Diabetologia. 1999;42(10):1240–3.View ArticlePubMedGoogle Scholar
  6. Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Magi R, Strawbridge RJ, Pers TH, Fischer K, Justice AE, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518(7538):187–96.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Jang YJ, Ryu HJ, Choi YO, Kim C, Leem CH, Park CS. Improvement of insulin sensitivity by chelation of intracellular Ca2+ in high-fat-fed rats. Metabolism. 2002;51(7):912–8.View ArticlePubMedGoogle Scholar
  8. Yang C, Watson RT, Elmendorf JS, Sacks DB, Pessin JE. Calmodulin antagonists inhibit insulin-stimulated GLUT4 (glucose transporter 4) translocation by preventing the formation of phosphatidylinositol 3,4,5-trisphosphate in 3T3L1 adipocytes. Mol Endocrinol. 2000;14(2):317–26.View ArticlePubMedGoogle Scholar
  9. Contreras-Ferrat AE, Toro B, Bravo R, Parra V, Vasquez C, Ibarra C, Mears D, Chiong M, Jaimovich E, Klip A, et al. An inositol 1,4,5-triphosphate (IP3)-IP3 receptor pathway is required for insulin-stimulated glucose transporter 4 translocation and glucose uptake in cardiomyocytes. Endocrinology. 2010;151(10):4665–77.View ArticlePubMedGoogle Scholar
  10. Lanner JT, Katz A, Tavi P, Sandstrom ME, Zhang SJ, Wretman C, James S, Fauconnier J, Lannergren J, Bruton JD et. al. The role of Ca2+ influx for insulin-mediated glucose uptake in skeletal muscle. Diabetes 2006;55(7): 2077-2083.Google Scholar
  11. Li Y, Wang P, Xu J, Gorelick F, Yamazaki H, Andrews N, Desir GV. Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII. Biochem Biophys Res Commun. 2007;362(3):658–64.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Bose A, Guilherme A, Robida SI, Nicoloro SM, Zhou QL, Jiang ZY, Pomerleau DP, Czech MP. Glucose transporter recycling in response to insulin is facilitated by myosin Myo1c. Nature. 2002;420(6917):821–4.View ArticlePubMedGoogle Scholar
  13. Chen XW, Leto D, Chiang SH, Wang Q, Saltiel AR. Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. Dev Cell. 2007;13(3):391–404.View ArticlePubMedGoogle Scholar
  14. Yip MF, Ramm G, Larance M, Hoehn KL, Wagner MC, Guilhaus M, James DE. CaMKII-mediated phosphorylation of the myosin motor Myo1c is required for insulin-stimulated GLUT4 translocation in adipocytes. Cell Metab. 2008;8(5):384–98.View ArticlePubMedGoogle Scholar
  15. Wang C, Chi Y, Li J, Miao Y, Li S, Su W, Jia S, Chen Z, Du S, Zhang X, et al. FAM3A activates PI3K p110alpha/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis. Hepatology. 2014;59(5):1779–90.View ArticlePubMedGoogle Scholar
  16. Dyck DJ. Adipokines as regulators of muscle metabolism and insulin sensitivity. Appl Physiol Nutr Metab. 2009;34(3):396–402.View ArticlePubMedGoogle Scholar
  17. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8(11):1288–95.View ArticlePubMedGoogle Scholar
  18. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, et al. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca2+ and AMPK/SIRT1. Nature. 2010;464(7293):1313–9.View ArticlePubMedGoogle Scholar
  19. Bi J, Wang W, Liu Z, Huang X, Jiang Q, Liu G, Wang Y. Seipin promotes adipose tissue fat storage through the ER Ca2+-ATPase SERCA. Cell Metab. 2014;19(5):861–71.View ArticlePubMedGoogle Scholar
  20. Subramanian M, Metya SK, Sadaf S, Kumar S, Schwudke D, Hasan G. Altered lipid homeostasis in drosophila InsP3 receptor mutants leads to obesity and hyperphagia. Dis Model Mech. 2013;6(3):734–44.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Baumbach J, Hummel P, Bickmeyer I, Kowalczyk KM, Frank M, Knorr K, Hildebrandt A, Riedel D, Jackle H, Kuhnlein RP. A drosophila in vivo screen identifies store-operated calcium entry as a key regulator of adiposity. Cell Metab. 2014;19(2):331–43.View ArticlePubMedGoogle Scholar
  22. Maus M, Cuk M, Patel B, Lian J, Ouimet M, Kaufmann U, Yang J, Horvath R, Hornig-Do HT, Chrzanowska-Lightowlers ZM, et al. Store-operated Ca2+ entry controls induction of lipolysis and the transcriptional reprogramming to lipid metabolism. Cell Metab. 2017;25(3):698–712.View ArticlePubMedGoogle Scholar
  23. Drago I, Pizzo P, Pozzan T. After half a century mitochondrial calcium in- and efflux machineries reveal themselves. EMBO J. 2011;30(20):4119–25.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Rasola A, Bernardi P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis. 2007;12(5):815–33.View ArticlePubMedGoogle Scholar
  25. Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol. 2012;13(9):566–78.View ArticlePubMedGoogle Scholar
  26. Phillips MJ, Voeltz GK. Structure and function of ER membrane contact sites with other organelles. Nat Rev Mol Cell Biol. 2016;17(2):69–82.View ArticlePubMedGoogle Scholar
  27. Duchen MR, Verkhratsky A, Muallem S. Mitochondria and calcium in health and disease. Cell Calcium. 2008;44(1):1–5.View ArticlePubMedGoogle Scholar
  28. Parone PA, Da Cruz S, Han JS, McAlonis-Downes M, Vetto AP, Lee SK, Tseng E, Cleveland DW. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J Neurosci. 2013;33(11):4657–71.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Kamer KJ, Mootha VK. The molecular era of the mitochondrial calcium uniporter. Nat Rev Mol Cell Biol. 2015;16(9):545–53.View ArticlePubMedGoogle Scholar
  30. Mammucari C, Raffaello A, Vecellio Reane D, Rizzuto R. Molecular structure and pathophysiological roles of the mitochondrial calcium uniporter. Biochim Biophys Acta. 2016;1863(10):2457–64.View ArticlePubMedGoogle Scholar
  31. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011;476(7360):341–5.View ArticlePubMedPubMed CentralGoogle Scholar
  32. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011;476(7360):336–40.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, Checchetto V, Moro S, Szabo I, Rizzuto R. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J. 2013;32(17):2362–76.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, et al. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science. 2013;342(6164):1379–82.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Vais H, Mallilankaraman K, Mak DO, Hoff H, Payne R, Tanis JE, Foskett JK. EMRE is a matrix Ca2+ sensor that governs gatekeeping of the mitochondrial Ca2+ uniporter. Cell Rep. 2016;14(3):403–10.View ArticlePubMedPubMed CentralGoogle Scholar
  36. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature. 2010;467(7313):291–6.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot J, Speciner L, et al. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One. 2013;8(2):e55785.View ArticlePubMedPubMed CentralGoogle Scholar
  38. Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell. 2014;53(5):726–37.View ArticlePubMedPubMed CentralGoogle Scholar
  39. Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, Fergusson MM, Rovira, II, Allen M, Springer DA et. al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 2013;15(12):1464-1472.Google Scholar
  40. Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, et al. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell. 2012;151(3):630–44.View ArticlePubMedPubMed CentralGoogle Scholar
  41. Alam MR, Groschner LN, Parichatikanond W, Kuo L, Bondarenko AI, Rost R, Waldeck-Weiermair M, Malli R, Graier WF. Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial Ca2+ uniporter (MCU) contribute to metabolism- secretion coupling in clonal pancreatic beta-cells. J Biol Chem. 2012;287(41):34445–54.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Samanta K, Douglas S, Parekh AB. Mitochondrial calcium uniporter MCU supports cytoplasmic Ca2+ oscillations, store-operated Ca2+ entry and Ca2+-dependent gene expression in response to receptor stimulation. PLoS One. 2014;9(7):e101188.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Deak AT, Blass S, Khan MJ, Groschner LN, Waldeck-Weiermair M, Hallstrom S, Graier WF, Malli R. IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. J Cell Sci. 2014;127(Pt 13):2944–55.View ArticlePubMedPubMed CentralGoogle Scholar
  44. Rimessi A, Bezzerri V, Patergnani S, Marchi S, Cabrini G, Pinton P. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis. Nat Commun. 2015;6:6201.View ArticlePubMedGoogle Scholar
  45. Wu Y, Rasmussen TP, Koval OM, Joiner ML, Hall DD, Chen B, Luczak ED, Wang Q, Rokita AG, Wehrens XH, et al. The mitochondrial uniporter controls fight or flight heart rate increases. Nat Commun. 2015;6:6081.View ArticlePubMedPubMed CentralGoogle Scholar
  46. Mammucari C, Gherardi G, Zamparo I, Raffaello A, Boncompagni S, Chemello F, Cagnin S, Braga A, Zanin S, Pallafacchina G, et al. The mitochondrial calcium uniporter controls skeletal muscle trophism in vivo. Cell Rep. 2015;10(8):1269–79.View ArticlePubMedPubMed CentralGoogle Scholar
  47. Logan CV, Szabadkai G, Sharpe JA, Parry DA, Torelli S, Childs AM, Kriek M, Phadke R, Johnson CA, Roberts NY, et al. Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet. 2014;46(2):188–93.View ArticlePubMedGoogle Scholar
  48. Liu JC, Liu J, Holmstrom KM, Menazza S, Parks RJ, Fergusson MM, Yu ZX, Springer DA, Halsey C, Liu C, et al. MICU1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload. Cell Rep. 2016;16(6):1561–73.View ArticlePubMedPubMed CentralGoogle Scholar
  49. Antony AN, Paillard M, Moffat C, Juskeviciute E, Correnti J, Bolon B, Rubin E, Csordas G, Seifert EL, Hoek JB, et al. MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration. Nat Commun. 2016;7:10955.View ArticlePubMedPubMed CentralGoogle Scholar
  50. Quiros PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016;17(4):213–26.View ArticlePubMedGoogle Scholar
  51. Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders - a step towards mitochondria based therapeutic strategies. Biochim Biophys Acta. 2017;1863(5):1066–77.View ArticlePubMedGoogle Scholar
  52. Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93(4):884S–90.View ArticlePubMedPubMed CentralGoogle Scholar
  53. Jensen B, Farach-Carson MC, Kenaley E, Akanbi KA. High extracellular calcium attenuates adipogenesis in 3T3-L1 preadipocytes. Exp Cell Res. 2004;301(2):280–92.View ArticlePubMedGoogle Scholar
  54. Liu L, Clipstone NA. Prostaglandin F2α inhibits adipocyte differentiation via a Gαq-calcium-calcineurin-dependent signaling pathway. J Cell Biochem. 2007;100(1):161–73.View ArticlePubMedGoogle Scholar
  55. Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, et al. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 2007;100(7):1063–70.View ArticlePubMedGoogle Scholar
  56. Ntambi JM, Takova T. Role of Ca2+ in the early stages of murine adipocyte differentiation as evidenced by calcium mobilizing agents. Differentiation. 1996;60(3):151–8.PubMedGoogle Scholar
  57. Neal JW, Clipstone NA. Calcineurin mediates the calcium-dependent inhibition of adipocyte differentiation in 3T3-L1 cells. J Biol Chem. 2002;277(51):49776–81.View ArticlePubMedGoogle Scholar
  58. Lin F, Ribar TJ, Means AR. The Ca2+/calmodulin-dependent protein kinase kinase, CaMKK2, inhibits preadipocyte differentiation. Endocrinology. 2011;152(10):3668–79.View ArticlePubMedPubMed CentralGoogle Scholar
  59. Szabo E, Qiu Y, Baksh S, Michalak M, Opas M. Calreticulin inhibits commitment to adipocyte differentiation. J Cell Biol. 2008;182(1):103–16.View ArticlePubMedPubMed CentralGoogle Scholar
  60. Wang CH, Chen YF, Wu CY, Wu PC, Huang YL, Kao CH, Lin CH, Kao LS, Tsai TF, Wei YH. Cisd2 modulates the differentiation and functioning of adipocytes by regulating intracellular Ca2+ homeostasis. Hum Mol Genet. 2014;23(18):4770–85.View ArticlePubMedGoogle Scholar
  61. Suarez J, Hu Y, Makino A, Fricovsky E, Wang H, Dillmann WH. Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor a in cardiomyocytes. Am J Physiol Cell Physiol. 2008;295(6):C1561–8.View ArticlePubMedPubMed CentralGoogle Scholar
  62. Gao CL, Zhu C, Zhao YP, Chen XH, Ji CB, Zhang CM, Zhu JG, Xia ZK, Tong ML, Guo XR. Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol. 2010;320(1-2):25–33.View ArticlePubMedGoogle Scholar
  63. Chemello F, Mammucari C, Gherardi G, Rizzuto R, Lanfranchi G, Cagnin S. Gene expression changes of single skeletal muscle fibers in response to modulation of the mitochondrial calcium uniporter (MCU). Genomics Data. 2015;5:64–7.View ArticlePubMedPubMed CentralGoogle Scholar
  64. Theurey P, Rieusset J. Mitochondria-associated membranes response to nutrient availability and role in metabolic diseases. Trends Endocrinol Metab. 2017;28(1):32–45.View ArticlePubMedGoogle Scholar
  65. Sala-Vila A, Navarro-Lerida I, Sanchez-Alvarez M, Bosch M, Calvo C, Lopez JA, Calvo E, Ferguson C, Giacomello M, Serafini A, et al. Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice. Sci Rep. 2016;6:27351.View ArticlePubMedPubMed CentralGoogle Scholar
  66. Rieusset J. Endoplasmic reticulum-mitochondria calcium signaling in hepatic metabolic diseases. Biochim Biophys Acta. 2017;1864(6):865–76.View ArticlePubMedGoogle Scholar
  67. Leem J, Koh EH. Interaction between mitochondria and the endoplasmic reticulum: implications for the pathogenesis of type 2 diabetes mellitus. Exp Diabetes Res. 2012;2012:242984.View ArticlePubMedGoogle Scholar
  68. Rodriguez-Arribas M, Yakhine-Diop SM, Pedro JM, Gomez-Suaga P, Gomez-Sanchez R, Martinez-Chacon G, Fuentes JM, Gonzalez-Polo RA, Niso-Santano M. Mitochondria-associated membranes (MAMs): overview and its role in Parkinson's disease. Mol Neurobiol. 2016; [Epub ahead of print]Google Scholar
  69. Tubbs E, Theurey P, Vial G, Bendridi N, Bravard A, Chauvin MA, Ji-Cao J, Zoulim F, Bartosch B, Ovize M, et al. Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance. Diabetes. 2014;63(10):3279–94.View ArticlePubMedGoogle Scholar
  70. Theurey P, Tubbs E, Vial G, Jacquemetton J, Bendridi N, Chauvin MA, Alam MR, Le Romancer M, Vidal H, Rieusset J. Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver. J Mol Cell Biol. 2016;8(2):129–43.View ArticlePubMedGoogle Scholar
  71. Rieusset J, Fauconnier J, Paillard M, Belaidi E, Tubbs E, Chauvin MA, Durand A, Bravard A, Teixeira G, Bartosch B, et al. Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance. Diabtologia. 2016;59(3):614–23.View ArticleGoogle Scholar
  72. Arruda AP, Pers BM, Parlakgul G, Guney E, Inouye K, Hotamisligil GS. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med. 2014;20(12):1427–35.View ArticlePubMedPubMed CentralGoogle Scholar
  73. Chen YF, Kao CH, Chen YT, Wang CH, Wu CY, Tsai CY, Liu FC, Yang CW, Wei YH, Hsu MT, et al. Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev. 2009;23(10):1183–94.View ArticlePubMedPubMed CentralGoogle Scholar
  74. Chang NC, Nguyen M, Bourdon J, Risse PA, Martin J, Danialou G, Rizzuto R, Petrof BJ, Shore GC. Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle. Hum Mol Genet. 2012;21(10):2277–87.View ArticlePubMedGoogle Scholar
  75. Adam-Vizi V, Starkov AA. Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis. 2010;20(Suppl 2):S413–26.View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© The Author(s). 2017

Advertisement