Could Lower Testosterone in Older Men Explain Higher COVID-19 Morbidity and Mortalities?

The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection’s outcome and might be related to a dysfunctional cell Ca2+ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca2+-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca2+ concentrations.

The Transient Receptor Potential Channel Yvc1 Deletion Recovers the Growth Defect of Calcineurin Mutant Under Endoplasmic Reticulum Stress in Candida albicans

Transient receptor potential (TRP) channel Yvc1 was related with hyphal growth, oxidative stress response, and pathogenicity. Calcineurin subunit Cnb1 was activated immediately in yeasts when exposed to severe stimulation. However, the relationship between Yvc1 and Cnb1-governed calcium ions and endoplasmic reticulum (ER) stress response remains unrevealed. In this study, we found that the mutant cnb1Δ/Δ was sensitive to TN, which was related with the overexpression of membrane calcium ion channels that could increase the cytosol calcium concentration. However, the growth of the cnb1Δ/Δyvc1Δ/Δ mutant was recovered and its cell vitality was better than the cnb1Δ/Δ strain. Meanwhile, the cellular calcium concentration was decreased and its fluctuation was weakened under ER stress in the cnb1Δ/Δyvc1Δ/Δ strain. To verify the regulation role of Yvc1 in the calcium concentration, we found that the addition of CaCl2 led to the worse viability, while the growth state was relieved under the treatment of EGTA in the cnb1Δ/Δ strain. In conclusion, the deletion of YVC1 could reduce the cellular calcium and relieve the ER stress sensitivity of the cnb1Δ/Δ strain. Thereby, our findings shed a novel light on the relationship between the Yvc1-governed cellular calcium concentration and ER stress response in C. albicans.

Functional Analysis of Rare Genetic Variants in the Negative Regulator of Intracellular Calcium Signaling RCAS/SLC10A7

The solute carrier family 10 member SLC10A7 is a negative regulator of intracellular calcium signaling (RCAS). In cell culture, SLC10A7 expression is negatively correlated with store-operated calcium entry (SOCE) via the plasma membrane. SLC10A7-deficient cells have significantly increased calcium influx after treatment with thapsigargin for depletion of ER calcium stores, whereas SLC10A7/RCAS overexpression limits calcium influx. Genetic variants in the human SLC10A7 gene are associated with skeletal dysplasia and amelogenesis imperfecta and reveal loss of function on cellular calcium influx. More recently, an additional disease-related genetic variant (P303L) as well as some novel genetic variants (V235F, T221M, I136M, L210F, P285L, and G146S) have been identified. In the present study, these variants were expressed in HEK293 cells to study their subcellular localization and their effect on cellular calcium influx. All variants were properly sorted to the ER compartment and closely co-localized with the STIM protein, a functional component of SOCE. The variants P303L and L210F showed significantly reduced effects on cellular calcium influx compared to the wild type but still maintained some degree of residual activity. This might explain the milder phenotype of patients bearing the P303L variant and might indicate disease potential for the newly identified L210F variant. In contrast, all other variants behaved like the wild type. In conclusion, the occurrence of variants in the SLC10A7 gene should be considered in patients with skeletal dysplasia and amelogenesis imperfecta. In addition to the already established variants, the present study identifies another potential disease-related SLC10A7/RCAS variant, namely, L210F, which seems to be most frequent in South Asian populations.

Abstract P467: Cardiac-specific Deletion Of Voltage Dependent Anion Channel 2 Leads To Dilated Cardiomyopathy By Altering Calcium Homeostasis

Voltage dependent anion channel 2 (VDAC2) is a mitochondrial outer membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in cellular calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. Previous literature suggests that improving mitochondrial calcium uptake via VDAC2 rescues arrhythmia phenotypes in genetic models of impaired cellular calcium signaling. However, the direct role of VDAC2 in intracellular calcium signaling and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac-specific deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium during development causes severe impairment in excitation-contraction coupling by reducing mitochondrial calcium uptake (n=3, p<0.05) and thereby impairing intracellular calcium signaling. VDAC2 knock-out mice showed a significant reduction in RYR-mediated calcium release (F/F 0 ) and rate of calcium uptake by SERCA2a [tau(msec)] compared to control mice (N=3, WT=54, KO=38, p<0.0001 (F/F 0 ) and p<0.05 (tau)). We also observed adverse cardiac remodeling which progressed to severe dilated cardiomyopathy and death (N=6, p<0.0001). Reintroducing VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype evident from improvement in ejection fraction and fractional shortening (n=3, p<0.05). Improving mitochondrial calcium uptake via VDAC2 using a VDAC2 agonist efsevin, increased cardiac contractile force in a mouse model of pressure-overload induced heart failure (N=8, n=22, p<0.05). In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing mitochondrial and cellular calcium signaling. Through this role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

Exploring the Hypothesis of a Schizophrenia and Bipolar Disorder Continuum: Biological, Genetic and Pharmacologic Data

: Present time nosology has its roots in Kraepelin’s demarcation of schizophrenia and bipolar disorder. However, accumulating evidence has shed light on several commonalities between the two disorders, and some authors have advocated for the consideration of a disease continuum. Here, we review previous genetic, biological and pharmacological findings that provide the basis for this conceptualization. There is a cross-disease heritability, and they share single-nucleotide polymorphisms in some common genes. EEG and imaging patterns have a number of similarities, namely reduced white matter integrity and abnormal connectivity. Dopamine, serotonin, GABA and glutamate systems have dysfunctional features, some of which are identical among the disorders. Finally, cellular calcium regulation and mitochondrial function are, also, impaired in the two.

Cellular Calcium Levels Influenced by NCA-2 Impact Circadian Period Determination in Neurospora

Circadian rhythms are based on cell-autonomous, auto-regulatory feedback loops formed by interlocked positive and negative arms, and they regulate myriad molecular and cellular processes in most eukaryotes, including fungi. Intracellular calcium signaling is also a process that impacts a broad range of biological events in most eukaryotes.