The psychiatric risk gene Cacna1c regulates mitochondrial function in cellular stress responses

Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness, and their pathophysiology involves complex interactions between genetic and environmental risk factors. However, the underlying mechanisms explaining how genetic and environmental alterations affect the risk for psychiatric disorders are still largely unknown. Confirmed by several genome-wide association studies over the past ten years, CACNA1C represents one of the strongest and most replicable psychiatric risk genes. Besides genetic predispositions, environmental influences such as childhood maltreatment or chronic stress also contribute to disease vulnerability. In addition, increasing evidence suggests a crucial role for mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation in the development of major neuropsychiatric disorders. Furthermore, mitochondrial dysfunction in peripheral blood mononuclear cells (PBMCs) is currently being discussed as a potential biomarker for affective disorders supporting early diagnosis, control of disease progression, and evaluation of treatment response. In a translational setting, the present project focused on the effects of defined gene-environment interactions on brain mitochondrial integrity and function in order to provide new insights into pathophysiological mechanisms of affective disorders and to identify novel therapeutic targets with potential relevance for future treatment strategies. Using immortalized mouse hippocampal HT22 cells, a well-established model system to investigate glutamate-mediated oxidative stress, it was demonstrated that both siRNA-mediated Cacna1c gene silencing and L-type calcium channel (LTCC) blockade with nimodipine significantly prevented the glutamate-mediated rise in lipid peroxidation, excessive ROS formation, collapse of mitochondrial membrane potential, loss of ATP, reduction in mitochondrial respiration, and ultimately neuronal cell death. Moreover, both Cacna1c knockdown and pharmacological LTCC inhibition altered CaV1.2-dependent gene transcription, thereby suppressing the glutamate-induced expression of the inner mitochondrial membrane calcium uptake protein MCU. Accordingly, downregulation of Cacna1c substantially diminished the elevation in mitochondrial calcium levels after glutamate treatment. In the employed paradigm of oxidative glutamate toxicity, Cacna1c depletion also protected against detrimental mitochondrial fission and stimulated mitochondrial biogenesis without affecting mitophagy, thus promoting the turnover of mitochondria and preventing the accumulation of dysfunctional mitochondria in neuronal HT22 cells. These data imply that upstream genetic modifications, e.g. reduced CACNA1C expression, converge to control mitochondrial function, resulting in cellular resilience against oxidative stress. In primary cortical rat neurons, heterozygous Cacna1c knockout partially reduced Cacna1c expression but had no impact on either initial increase in [Ca2+]i or delayed perturbations in mitochondrial bioenergetics, ATP levels, and cell viability in response to glutamate-mediated excitotoxicity. Furthermore, Cacna1c mRNA and protein expression levels were subject to strong regulation and degradation in this model of neuronal excitotoxicity. Partial neuroprotection against long-term glutamate toxicity by pharmacological LTCC blockade highlighted a potential dose-effect-dependency and the involvement of LTCCs in this cell death pathway. In primary rat microglia cultures, both Cacna1c haploinsufficiency and nimodipine treatment were associated with reduced morphological changes and glycolytic metabolism upon lipopolysaccharide (LPS) stimulation. The LPS-induced shift from oxidative phosphorylation towards glycolysis seems essential for the inflammatory response, since the downstream release of NO, IL-1α, IL-1β, IL-6, IL-10, and TNF-α was also decreased in heterozygous Cacna1c as well as nimodipine-treated microglial cells. These results indicate a major functional role for CaV1.2-dependent signaling in the pro-inflammatory activation of microglia, the innate immune cells of the central nervous system. By simulating the interaction of psychiatric disease-relevant genetic and environmental factors in vivo, the present study additionally evaluated their potential effect on brain mitochondrial function using a constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment during the juvenile developmental period. In this specific gene-environment setting, isolated mitochondria from prefrontal cortex and hippocampus, both representing particularly susceptible brain regions in neuropsychiatric disorders, did not reveal considerable differences in mitochondrial bioenergetics, respiratory chain complex protein levels, superoxide formation, and membrane potential between the investigated conditions. Finally, mitochondrial function was investigated in human PBMCs from probands recruited in the Marburg/Münster Affective Disorders Cohort Study (MACS). However, neither a family history of psychiatric disorders nor an experience of maltreatment during childhood had a significant effect on mitochondrial superoxide levels and respiratory parameters in PBMCs from healthy female subjects. Consequently, further research is required in order to shed more light on the early pathological mechanisms underlying neuropsychiatric disorders. Overall, the present findings suggest that the GWAS-confirmed psychiatric risk gene CACNA1C plays a significant role in oxidative stress as well as neuroinflammatory pathways with particular impact on mitochondrial integrity and function, thereby adding to a better understanding of the intracellular processes likely involved in the pathophysiology of CACNA1C-associated disorders. Thus, modulating L-type calcium signaling may offer an effective therapeutic strategy in psychiatric disorders, where neuronal atrophy and inflammation contribute to disease pathophysiology

Mitochondria, Microglia, and the Immune System—How Are They Linked in Affective Disorders?

Major depressive disorder (MDD) is a severe mood disorder and frequently associated with alterations of the immune system characterized by enhanced levels of circulating pro-inflammatory cytokines and microglia activation in the brain. Increasing evidence suggests that dysfunction of mitochondria may play a key role in the pathogenesis of MDD. Mitochondria are regulators of numerous cellular functions including energy metabolism, maintenance of redox and calcium homeostasis, and cell death and therefore modulate many facets of the innate immune response. In depression-like behavior of rodents, mitochondrial perturbation and release of mitochondrial components have been shown to boost cytokine production and neuroinflammation. On the other hand, pro-inflammatory cytokines may influence mitochondrial functions such as oxidative phosphorylation, production of adenosine triphosphate, and reactive oxygen species, thereby aggravating inflammation. There is strong interest in a better understanding of immunometabolic pathways in MDD that may serve as diagnostic markers and therapeutic targets. Here, we review the interaction between mitochondrial metabolism and innate immunity in the pathophysiology of MDD. We specifically focus on immunometabolic processes that govern microglial and peripheral myeloid cell functions, both cellular components involved in neuroinflammation in depression-like behavior. We finally discuss microglial polarization and associated metabolic states in depression-associated behavior and in MDD

Cytochrome c Oxidase Inhibition by ATP Decreases Mitochondrial ROS Production

This study addresses the eventual consequence of cytochrome c oxidase (CytOx) inhibition by ATP at high ATP/ADP ratio in isolated rat heart mitochondria. Earlier, it has been demonstrated that the mechanism of allosteric ATP inhibition of CytOx is one of the key regulations of mitochondrial functions. It is relevant that aiming to maintain a high ATP/ADP ratio for the measurement of CytOx activity effectuating the enzymatic inhibition as well as mitochondrial respiration, optimal concentration of mitochondria is critically important. Likewise, only at this concentration, were the differences in ΔΨ(m) and ROS concentrations measured under various conditions significant. Moreover, when CytOx activity was inhibited in the presence of ATP, mitochondrial respiration and ΔΨ(m) both remained static, while the ROS production was markedly decreased. Consubstantial results were found when the electron transport chain was inhibited by antimycin A, letting only CytOx remain functional to support the energy production. This seems to corroborate that the decrease in mitochondrial ROS production is solely the effect of ATP binding to CytOx which results in static respiration as well as membrane potential

Interaction of the Psychiatric Risk Gene Cacna1c With Post-weaning Social Isolation or Environmental Enrichment Does Not Affect Brain Mitochondrial Bioenergetics in Rats

The pathophysiology of neuropsychiatric disorders involves complex interactions between genetic and environmental risk factors. Confirmed by several genome-wide association studies, Cacna1c represents one of the most robustly replicated psychiatric risk genes. Besides genetic predispositions, environmental stress such as childhood maltreatment also contributes to enhanced disease vulnerability. Both, Cacna1c gene variants and stressful life events are associated with morphological alterations in the prefrontal cortex and the hippocampus. Emerging evidence suggests impaired mitochondrial bioenergetics as a possible underlying mechanism of these regional brain abnormalities. In the present study, we simulated the interaction of psychiatric disease-relevant genetic and environmental factors in rodents to investigate their potential effect on brain mitochondrial function using a constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment. Mitochondria were isolated from the prefrontal cortex and the hippocampus to evaluate their bioenergetics, membrane potential, reactive oxygen species production, and respiratory chain complex protein levels. None of these parameters were considerably affected in this particular gene-environment setting. These negative results were very robust in all tested conditions demonstrating that Cacna1c depletion did not significantly translate into altered bioenergetic characteristics. Thus, further investigations are required to determine the disease-related effects on brain mitochondria

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation—A Retrospective International Multicenter Study

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. Methods: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) Score, and 30-day survival. Results: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic—AUROC) ranged between 0.548 and 0.605. Conclusions: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V-V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO

Prognostic impact of acute pulmonary triggers in patients with Takotsubo syndrome : new insights from the International Takotsubo Registry

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002). Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.C. T. has been supported by the H.H. Sheikh Khalifa binHamad Al-Thani Research Programme and the Swiss HeartFoundation. The InterTAK Registry is supported by the BissDavies Charitable Trust. L. S. M. has been supported by EUHORIZON 2020(SILICOFCM ID777204)info:eu-repo/semantics/publishedVersio

Ethnic comparison in takotsubo syndrome : novel insights from the International Takotsubo Registry

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes. Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients. Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients. Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.Open Access funding provided by Universität Zürich. CT has been supported by the H.H. Sheikh Khalifa bin Hamad Al-Thani Research Programme and the Swiss Heart Foundation. L.S.M. has been supported by EU HORIZON 2020 (SILICOFCM ID777204). J.R.G has received a grant “Filling the gap” from the University of Zurich. The InterTAK Registry is supported by The Biss Davies Charitable Trust.info:eu-repo/semantics/publishedVersio

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe