Impact of Intermittent Hypoxia Related to Obstructive Sleep Apnoea Syndrome on Low-Grade Inflammation in Hypertensive Patients: Potential Implications for Cardiovascular Risk.

There is evidence for a particular relationship between low-grade inflammation (LGI) and intermittent hypoxia (IH) related to obstructive sleep apnoea syndrome (OSAS). However, despite the potential deleterious cardiovascular consequences associated with this LGI in hypertensive patients, few studies have investigated the impact of IH related to OSAS on CRP levels in this subpopulation. In total, 1404 hypertensive patients were selected retrospectively from the Sleep Laboratory database. CRP levels ≥3 mg/L but <10 mg/L were used as cut-offs to identify hypertensive patients with LGI. Logistic regressions were conducted to examine the risk of LGI associated with IH related to OSAS in hypertensive patients. LGI was frequent (33.8%) in hypertensive patients. After adjustment for confounders, multivariate logistic regressions revealed that only moderate to severe OSAS (apnoea-hypopnoea index ≥ 15/h) with high IH (oxygen desaturation index ≥ 15/h) [OR 1.51 (95% CI 1.06-2.14)] was significantly associated with LGI in hypertensive patients (p-value = 0.045). Consistent with our hypothesis, our results demonstrated the existence of a particular subtype of hypertensive patients at high cardiovascular risk characterised by the presence of LGI induced by IH hypoxia related to moderate to severe OSAS, which justifies the establishment of adequate management of this pathology to allow better cardiovascular prevention in this subpopulation.

Cardiovascular Outcome in Patients with Major Depression: Role of Obstructive Sleep Apnea Syndrome, Insomnia Disorder, and COMISA.

In this study, the 10-year cardiovascular risk associated with comorbid sleep disorders (insomnia disorder, obstructive sleep apnea syndrome, and COMISA [comorbid insomnia and sleep apnea]) was investigated for patients with major depression. To enable our analysis, 607 patients with major depression were selected from the data register of the Sleep Unit. High 10-year cardiovascular risk was considered present when the Framingham Risk Score was ≥10%. The 10-year cardiovascular risk associated with comorbid sleep disorders has been assessed using logistic regression analyzes. High 10-year cardiovascular risk is significant (40.4%) in patients with major depression. After successive introduction of the different confounders, multivariate logistic regressions showed that for patients with major depression high 10-year cardiovascular risk was significantly associated with COMISA but was not significantly associated with insomnia disorder or obstructive sleep apnea syndrome alone. Thus, these results highlight the existence of a negative synergistic action between insomnia disorder and obstructive sleep apnea syndrome on the 10-year cardiovascular risk in patients with major depression, which demonstrates the importance of researching and treating COMISA to improve the prognosis of this specific population subgroup characterized by higher cardiovascular morbidity and mortality.

Suicidal Ideations in Major Depressed Subjects: Role of the Temporal Dynamics of Anhedonia.

Given the limited data available in the literature, the aim of this study was to investigate the potential role played by the temporal dynamics of anhedonia (lifelong anhedonia and recent changes in anhedonia) in the occurrence of suicidal ideations in major depressed subjects. The clinical data of 285 major depressed subjects recruited from the database of the Erasme Hospital Sleep Laboratory were analyzed. A score on item nine of the Beck Depression Inventory (BDI-II) ≥1 and/or an identification during the systematic psychiatric assessment were used to determine the presence of suicidal ideations. The association between anhedonia complaints (lifelong anhedonia and recent change in anhedonia) and suicidal ideations in major depressed subjects was assessed by logistic regression analyzes. The prevalence of suicidal ideations was 39.3% in our sample of major depressed subjects. After adjusting for the main confounding factors, multivariate logistic regression analysis demonstrated that unlike lifelong anhedonia, only recent changes in anhedonia were a risk factor for suicidal ideations in major depressed subjects. Given this potential involvement of the recent change in anhedonia in the occurrence of suicidal ideations in major depressed subjects, it seems essential to better identify and adequately manage this specific form of anhedonia in order to open new perspectives for the prevention of suicide in this particular sub-population.

10-Year Risk for Cardiovascular Disease Associated with COMISA (Co-Morbid Insomnia and Sleep Apnea) in Hypertensive Subjects.

Due to the few studies available, this study aimed to investigate the 10-year risk for cardiovascular disease (CVD) associated with COMISA (co-morbid insomnia and sleep apnea) in hypertensive subjects. Clinical data of 1009 hypertensive subjects extracted from the Sleep Laboratory database were analyzed. Framingham Risk Score ≥ 10% was used as a cut-off to identify hypertensive subjects with high 10-year risk for CVD. The association between 10-year risk for CVD and COMISA was investigated using logistic regression analyses. 65.3% of hypertensive subjects from our sample presented a high 10-year risk for CVD. After controlling for major confounding factors, multivariate logistic regression analyses demonstrated that unlike its components present separately, COMISA was significantly associated with high 10-year risk for CVD in hypertensive subjects (OR 1.88, 95% CI 1.01-3.51). In this study, we have demonstrated that the negative synergy between obstructive sleep apnea syndrome and insomnia disorder seems to play a central role in the 10-year risk for CVD in hypertensive subjects, which seems to indicate that the establishment of a systematic research and an adapted treatment of COMISA could open new perspectives to promote a better cardiovascular outcome in this specific subgroup of patients.

Prevalence and Relationships between Alexithymia, Anhedonia, Depression and Anxiety during the Belgian COVID-19 Pandemic Lockdown.

Alexithymia and anhedonia are associated with psychiatric disorders, such as depression and anxiety. The COVID-19 pandemic lead to a significant deterioration in the mental health of the population. It is therefore important to examine the effects of lockdown on alexithymia and anhedonia and their relationships with anxiety and depression. We compared the scores and characteristics of 286 patients divided into two groups: one before lockdown (group 1, N = 127), the other during the progressive lockdown release (group 2, N = 159). The groups were homogeneous in terms of age, sex ratio, socio-professional categories, and somatic and psychiatric comorbidities. The groups were compared on the Toronto Alexithymia Scale (TAS-20) measuring alexithymia, the Beck Depression Inventory (BDI-II) measuring depression, the anhedonia subscale of the BDI-II measuring state-anhedonia and the State Trait Anxiety Inventory (STAI) measuring state and trait anxiety. The ratio of alexithymic subjects in group 1 is 22.83% to 33.33% in group 2 (p-value = 0.034). This suggests a significant increase in the number of alexithymic patients after lockdown. We did not observe any difference in the proportion of depressed and anxious subjects before or after lockdown. Among the different scales, higher scores were only found on the cognitive factor of alexithymia on group 2 comparatively to group 1. This study indicates an increase in the proportion of alexithymic subjects following lockdown. Unexpectedly, this was unrelated to depression, anxiety or anhedonia levels, which remained stable. Further studies are needed to confirm this result and to evaluate precisely which factors related to the lockdown context are responsible for such an increase.

Suicidal Ideation in Major Depressed Individuals: Role of Type D Personality.

Major depressed individuals are a subpopulation at high-risk of suicide. However, despite the evidence for a particular relationship between suicidal ideation (SI) and type D personality, few studies have investigated the role played by this personality structure in the occurrence of SI in major depressed individuals. Data from 318 major depressed individuals recruited from the clinical database of the Sleep Laboratory were analysed. Suicidal ideation was considered present if the score in item 9 of the Beck Depression Inventory (BDI-II) was ≥1 and/or if they were highlighted during the systematic psychiatric assessment conducted on admission to the Sleep Laboratory. Logistic regression analyses were used to determine the risk of SI associated with type D personality in major depressed individuals. The prevalence of suicidal ideation was 38.4% in our sample of major depressed individuals. After adjusting for major confounding factors, multivariate logistic regression analyses demonstrated that type D personality was a risk factor for SI in major depressed individuals. Thus, given the potential role played by type D personality in the occurrence of SI in major depressed individuals, it seems necessary to more systematically research and adequately manage this personality structure to allow for a better prevention of suicidal behaviours in this subpopulation.

Risk of Cardiovascular Disease in Apnoeic Individuals: Role of Comorbid Insomnia Disorder.

Given the limited data available, the aim of this study was to examine the 10-year cardiovascular disease (CVD) risk associated with comorbid insomnia disorder and its specific subtypes in apnoeic individuals. Data from 1104 apnoeic individuals recruited from the database of the Erasme Hospital Sleep Laboratory were analysed. Only apnoeic individuals with a Framingham Risk Score ≥10% were included in the group at moderate-to-high 10-year CVD risk. Logistic regression analyses were conducted to examine the risk of 10-year CVD risk associated with comorbid insomnia disorder and its specific subtypes in apnoeic individuals. Moderate-to-high 10-year CVD risk was present in 59.6% of the apnoeic individuals in our sample. After adjustment for the main confounding factors, multivariate logistic regression analyses revealed that comorbid insomnia disorder and, more particularly, its subtype with short sleep duration were significantly associated with moderate-to-high 10-year CVD risk in apnoeic individuals. In this study, we demonstrate that comorbid insomnia disorder and, more specifically, its subtype with short sleep duration appear to have a negative cumulative effect on 10-year CVD risk in apnoeic individuals, which justifies more systematic research and adequate therapeutic management of this disorder to allow for better cardiovascular disease prevention in this particular subpopulation.

Impact of Alexithymia on the Lipid Profile in Major Depressed Individuals.

Background: The cooccurrence of major depression and dyslipidaemia is associated with negative cardiovascular outcome, which seems to justify a better identification of the factors favouring the development of dyslipidaemia in major depressed individuals. In the literature, there are arguments in favour of a special relationship between dyslipidaemia and alexithymia. However, despite a high prevalence of alexithymia in major depressed individuals, no study has investigated the impact of this personality trait on the lipid profile in this particular subpopulation. Given these elements, the aim of this study was therefore to investigate the risk of dyslipidaemia associated with alexithymia in major depressed individuals to allow better cardiovascular prevention in this subpopulation. Subjects and Methods. Demographic and polysomnographic data from 242 major depressed individuals recruited from the clinical database of the sleep laboratory were analysed. Only individuals with a diagnosis of dyslipidaemia according to the diagnostic criteria of the International Diabetes Federation at admission were included in the "dyslipidaemia" group. Logistic regression analyses were used to determine the risk of dyslipidaemia associated with alexithymia in major depressed individuals. Results: The prevalence of dyslipidaemia was 43.8% in our sample of major depressed individuals. After adjusting for the main confounding factors, multivariate logistic regression analyses demonstrated that alexithymia was a risk factor for dyslipidaemia in major depressed individuals. Conclusions: In this study, we found that alexithymia is a risk factor for dyslipidaemia in major depressed individuals, which seems to justify better identification and adequate management of this personality trait in order to allow a better lipid profile in this subpopulation at high cardiovascular risk.

The association between type 2 diabetes and anhedonic subtype of major depression in hypertensive individuals.

Given the limited data in the literature, the aim of this study was to investigate the association between type 2 diabetes and anhedonic subtype of major depression in hypertensive individuals. Demographic and polysomnographic data from 323 hypertensive individuals recruited from the database of the Erasme Hospital Sleep Laboratory were analysed. Only individuals with a diagnosis of type 2 diabetes according to the diagnostic criteria of the American Diabetes Association at admission were included in the "diabetes group". Logistic regression analyses were used to study the association between type 2 diabetes and anhedonic subtype of major depression in hypertensive individuals. The rate of type 2 diabetes was 18.9% in our sample of hypertensive individuals. After adjusting for major confounding factors, multivariate logistic regression analyses demonstrated that unlike the non-anhedonic subtype of major depression, only the anhedonic subtype of major depression was significantly associated with higher likelihood of having type 2 diabetes in hypertensive individuals. In this study, the authors demonstrated that the anhedonic subtype of major depression is significantly associated with type 2 diabetes in hypertensive individuals, which could potentially open up new perspectives for the development of therapeutic strategies complementary to conventional treatments for type 2 diabetes in this subpopulation at high risk of complications related to the co-occurrence of this metabolic disorder.

Risk of current suicidal ideations associated with lifelong anhedonia and recent change of anhedonia in individuals with insomnia: A cross-sectional study.

BACKGROUND: Individuals with insomnia are a subpopulation at high-risk of suicide. However, despite the elements in favour of an implication of anhedonia in the occurrence of current suicidal ideations (SI), no study has investigated the role played by this affective symptom in the occurrence of current SI in individuals with insomnia. The aim of this study was to investigate the risk of current SI associated with lifelong anhedonia and recent change of anhedonia in individuals with insomnia. METHOD: Demographic and polysomnographic data from 493 individuals with insomnia selected retrospectively from the clinical database of the Erasme Hospital Sleep Laboratory were analysed. Current SI were considered present if the score in item 9 of the Beck Depression Inventory (BDI-II) was ≥1 and/or if they were highlighted during the systematic psychiatric assessment conducted on admission to the Sleep Laboratory. Logistic regression analyses were used to determine the risk of current SI associated with anhedonia in individuals with insomnia. RESULTS: The prevalence of current SI was 21.5% in our sample of individuals with insomnia. After adjusting for major confounding factors, multivariate logistic regression analyses demonstrated that unlike lifelong anhedonia, only recent change of anhedonia was a risk factor for current SI in individuals with insomnia. CONCLUSION: In this study, we demonstrated that in individuals with insomnia, recent change of anhedonia is a risk factor for current SI, which seems to justify more systematic research and adequate therapeutic management of this condition to allow better prevention in this particular subpopulation at high-risk of suicide.

The association between type 2 diabetes and major depression in apnoeic individuals.

Given the few studies available in the literature, the aim of this study was to investigate the association between type 2 diabetes and major depression in a large sample of apnoeic individuals. Demographic and polysomnographic data from 395 apnoeic individuals recruited from the clinical database of the Erasme Hospital Sleep Laboratory were analysed. Only individuals with a diagnosis of type 2 diabetes according to the diagnostic criteria of the American Diabetes Association at admission were included in the "diabetes" group. Logistic regression analyses were used to study the association between type 2 diabetes and major depression in apnoeic individuals. The prevalence of type 2 diabetes was 19.7% in our sample of apnoeic individuals. After adjusting for major confounding factors, multivariate logistic regression analyses demonstrated that unlike remitted major depression and mild major depression, only moderate to severe major depression was significantly associated with higher likelihood of type 2 diabetes in apnoeic individuals. In our study, we found that moderate to severe major depression is significantly associated with type 2 diabetes in apnoeic individuals, which seems to justify more systematic screening and adequate therapeutic management of this psychiatric disorder to allow better glycaemic control in this subpopulation at high risk of diabetic micro/macrovascular complications. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-021-00359-0.

Polysomnographic markers of suicidal ideation in untreated unipolar major depressed individuals.

Given the major role played by sleep in the particular relationship between suicidality and major depression, the aim of this study was to empirically identify polysomnographic markers specific to suicidal ideation in major depressed individuals in order to allow better suicide prevention in this high-risk subpopulation. Demographic and polysomnographic data from 190 individuals (34 healthy controls and 156 untreated unipolar major depressed individuals) recruited from the sleep laboratory database were analysed. Suicidal ideation were considered present if the score in item G of the Beck Depression Inventory was ≥1 and/or if they were highlighted during the systematic psychiatric assessment conducted on admission to the sleep laboratory. Independently of depression severity, major depressed individuals with suicidal ideation present a decrease in deep NREM sleep (slow-wave sleep) and an increase in light NREM sleep (stage 1 + stage 2) compared to those without suicidal ideation. There are no significant differences for the other polysomnographic parameters. In our study, we highlighted the existence of potential polysomnographic markers of suicidal ideation in untreated unipolar major depressed individuals, which seems to open up new perspectives for the identification and management of individuals at high-risk of suicide in this particular subpopulation.

Dual dynamics of mitochondrial permeability transition pore opening.

Mitochondria play an essential role in bioenergetics and cellular Ca[Formula: see text] handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca[Formula: see text] homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca[Formula: see text], we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca[Formula: see text] handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca[Formula: see text] in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship.

Intracellular Ca2+ signals are well organized in all cell types, and trigger a variety of vital physiological processes. The temporal and spatial characteristics of cytosolic Ca2+ increases are mainly governed by the fluxes of this ion across the membrane of the endoplasmic/sarcoplasmic reticulum and the plasma membrane. However, various Ca2+ transporters also allow for Ca2+ exchanges between the cytoplasm and mitochondria. Increases in mitochondrial Ca2+ 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 Ca2+ handling by mitochondria also shapes cytosolic Ca2+ signals. Indeed, the frequency, amplitude, and duration of cytosolic Ca2+ increases can be altered by modifying the rates of Ca2+ transport into, or from, mitochondria. In this review, we focus on the interplay between mitochondria and Ca2+ signaling, highlighting not only the consequences of cytosolic Ca2+ changes on mitochondrial Ca2+, but also how cytosolic Ca2+ dynamics is controlled by modifications of the Ca2+-handling properties and the metabolism of mitochondria.

Coding and decoding of oscillatory Ca2+ signals.

About 30 years after their first observation, Ca2+ oscillations are now recognised as a universal mechanism of signal transduction. These oscillations are driven by periodic cycles of release and uptake of Ca2+ between the cytoplasm and the endoplasmic reticulum. Their frequency often increases with the level of stimulation, which can be decoded by some molecules. However, it is becoming increasingly evident that the widespread core oscillatory mechanism is modulated in many ways, depending on the cell type and on the physiological conditions. Interplay with inositol 1,4,5-trisphosphate metabolism and with other Ca2+ stores as the extracellular medium or mitochondria can much affect the properties of these oscillations. In many cases, these finely tuned characteristics of Ca2+ oscillations impact the physiological response that is triggered by the signal. Moreover, oscillations are intrinsically irregular. This randomness can also be exploited by the cell. In this review, we discuss evidences of these additional manifestations of the versatility of Ca2+ signalling.

Modeling-Based Investigation of the Effect of Noise in Cellular Systems.

Noise is pervasive in cellular biology and inevitably affects the dynamics of cellular processes. Biological systems have developed regulatory mechanisms to ensure robustness with respect to noise or to take advantage of stochasticity. We review here, through a couple of selected examples, some insights on possible robustness factors and constructive roles of noise provided by computational modeling. In particular, we focus on (1) factors that likely contribute to the robustness of oscillatory processes such as the circadian clocks and the cell cycle, (2) how reliable coding/decoding of calcium-mediated signaling could be achieved in presence of noise and, in some cases, enhanced through stochastic resonance, and (3) how embryonic cell differentiation processes can exploit stochasticity to create heterogeneity in a population of identical cells.

Mitochondrial Ca2+ dynamics in cells and suspensions.

Mitochondria play a significant role in shaping cytosolic Ca2+ signals. Thus, transfer of Ca2+ across the mitochondrial membrane is much studied, not only in intact cells but also in artificial systems such as mitochondrial suspensions or permeabilised cells. Observed rates of Ca2+ changes vary by at least one order of magnitude. In this work, we investigate the relationship between the Ca2+ dynamics observed in various experimental conditions using a computational model calibrated on experimental data. Results confirm that mitochondrial Ca2+ exchange fluxes through the mitochondrial Ca2+ uniporter (MCU) and the Na+ /Ca2+ exchanger obey the same basic kinetics in cells and in suspensions, and emphasise the important role played by the high Ca2+ levels reached in mitochondria-associated endoplasmic reticulum membranes in intact cells. Tissue specificity can be ascribed to the different modes of regulation of the MCU by Ca2+ , probably related to the specific levels of expression of the Ca2+ sensing regulator subunit of this channel. The model emphasises the importance of mitochondrial density and buffering in controlling the rate of Ca2+ exchanges with mitochondria, as verified experimentally. Finally, we show that heterogeneity between individual mitochondria can explain the large range of amplitudes and rates of rise in mitochondrial Ca2+ concentration that have been observed experimentally.

The Shigella type III effector IpgD recodes Ca2+ signals during invasion of epithelial cells.

The role of second messengers in the diversion of cellular processes by pathogens remains poorly studied despite their importance. Among these, Ca2+ virtually regulates all known cell processes, including cytoskeletal reorganization, inflammation, or cell death pathways. Under physiological conditions, cytosolic Ca2+ increases are transient and oscillatory, defining the so-called Ca2+ code that links cell responses to specific Ca2+ oscillatory patterns. During cell invasion, Shigella induces atypical local and global Ca2+ signals. Here, we show that by hydrolyzing phosphatidylinositol-(4,5)bisphosphate, the Shigella type III effector IpgD dampens inositol-(1,4,5)trisphosphate (InsP3) levels. By modifying InsP3 dynamics and diffusion, IpgD favors the elicitation of long-lasting local Ca2+ signals at Shigella invasion sites and converts Shigella-induced global oscillatory responses into erratic responses with atypical dynamics and amplitude. Furthermore, IpgD eventually inhibits InsP3-dependent responses during prolonged infection kinetics. IpgD thus acts as a pathogen regulator of the Ca2+ code implicated in a versatility of cell functions. Consistent with this function, IpgD prevents the Ca2+-dependent activation of calpain, thereby preserving the integrity of cell adhesion structures during the early stages of infection.

At the cross-point of connexins, calcium, and ATP: blocking hemichannels inhibits vasoconstriction of rat small mesenteric arteries.

AIMS: Connexins form gap-junctions (GJs) that directly connect cells, thereby coordinating vascular cell function and controlling vessel diameter and blood flow. GJs are composed of two hemichannels contributed by each of the connecting cells. Hemichannels also exist as non-junctional channels that, when open, lead to the entry/loss of ions and the escape of ATP. Here we investigated cross-talk between hemichannels and Ca2+/purinergic signalling in controlling blood vessel contraction. We hypothesized that hemichannel Ca2+ entry and ATP release contributes to smooth muscle cell (SMC) Ca2+ dynamics, thereby influencing vessel contractility. We applied several peptide modulators of hemichannel function and inhibitors of Ca2+ and ATP signalling to investigate their influence on SMC Ca2+ dynamics and vessel contractility. METHODS AND RESULTS: Confocal Ca2+ imaging studies on small mesenteric arteries (SMAs) from rat demonstrated that norepinephrine-induced SMC Ca2+ oscillations were inhibited by blocking IP3 receptors with xestospongin-C and by interfering with hemichannel function, most notably by the specific Cx43 hemichannel blocking peptide TAT-L2 and by TAT-CT9 that promotes Cx43 hemichannel opening. Evidence for hemichannel involvement in SMC function was supported by the fact that TAT-CT9 significantly increased SMC resting cytoplasmic Ca2+ concentration, indicating it facilitated Ca2+ entry, and by the observation that norepinephrine-triggered vessel ATP release was blocked by TAT-L2. Myograph tension measurements on isolated SMAs showed significant inhibition of norepinephrine-triggered contractility by the ATP receptor antagonist suramin, but the strongest effect was observed with TAT-L2 that gave ∼80% inhibition at 37 °C. TAT-L2 inhibition of vessel contraction was significantly reduced in conditional Cx43 knockout animals, indicating the effect was Cx43 hemichannel-dependent. Computational modelling suggested these results could be explained by the opening of a single hemichannel per SMC. CONCLUSIONS: These results indicate that Cx43 hemichannels contribute to SMC Ca2+ dynamics and contractility, by facilitating Ca2+ entry, ATP release, and purinergic signalling.

Interplay Between Intracellular Ca(2+) Oscillations and Ca(2+)-stimulated Mitochondrial Metabolism.

Oscillations of cytosolic Ca(2+) concentration are a widespread mode of signalling. Oscillatory spikes rely on repetitive exchanges of Ca(2+) between the endoplasmic reticulum (ER) and the cytosol, due to the regulation of inositol 1,4,5-trisphosphate receptors. Mitochondria also sequester and release Ca(2+), thus affecting Ca(2+) signalling. Mitochondrial Ca(2+) activates key enzymes involved in ATP synthesis. We propose a new integrative model for Ca(2+) signalling and mitochondrial metabolism in electrically non-excitable cells. The model accounts for (1) the phase relationship of the Ca(2+) changes in the cytosol, the ER and mitochondria, (2) the dynamics of mitochondrial metabolites in response to cytosolic Ca(2+) changes, and (3) the impacts of cytosol/mitochondria Ca(2+) exchanges and of mitochondrial metabolism on Ca(2+) oscillations. Simulations predict that as expected, oscillations are slowed down by decreasing the rate of Ca(2+) efflux from mitochondria, but also by decreasing the rate of Ca(2+) influx through the mitochondrial Ca(2+) uniporter (MCU). These predictions were experimentally validated by inhibiting MCU expression. Despite the highly non-linear character of Ca(2+) dynamics and mitochondrial metabolism, bioenergetics were found to be robust with respect to changes in frequency and amplitude of Ca(2+) oscillations.