COVID-19 is a systemic infection that exerts significant impact on the metabolism. Yet, there is little information on how SARS-CoV-2 affects metabolism. Using NMR spectroscopy, we measured the metabolomic and lipidomic serum profile from 263 (training cohort) + 135 (validation cohort) symptomatic patients hospitalized after positive PCR testing for SARS-CoV-2 infection. We also established the profiles of 280 persons collected before the coronavirus pandemic started. Principal-component analysis discriminated both cohorts, highlighting the impact that the infection has on overall metabolism. The lipidomic analysis unraveled a pathogenic redistribution of the lipoprotein particle size and composition to increase the atherosclerotic risk. In turn, metabolomic analysis reveals abnormally high levels of ketone bodies (acetoacetic acid, 3-hydroxybutyric acid, and acetone) and 2-hydroxybutyric acid, a readout of hepatic glutathione synthesis and marker of oxidative stress. Our results are consistent with a model in which SARS-CoV-2 infection induces liver damage associated with dyslipidemia and oxidative stress.

Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA.

P53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized byO-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible ofO-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that theO-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

The off-patent marketed antifungal ciclopirox improves symptoms in a mouse model of congenital erythropoietic porphyria.

Significance: Ion channels are sophisticated proteins that exert control over a plethora of body functions. Specifically, the members of the Kv7 family are prominent components of the nervous systems, responsible for the ion fluxes that regulate the electrical signaling in neurons and cardiac myocytes. Albeit its relevance, there are still several questions, including the Ca ²⁺ /calmodulin (CaM)-mediated gating mechanism. We found that Ca ²⁺ binding to CaM triggers a segmental rotation that allosterically transmits the signal from the cytosol up to the transmembrane region. NMR-derived analysis of the dynamics demonstrates that it occurs through a conformational selection mechanism. Energetically, CaM association with the channel tunes the affinities of the CaM lobes (calmodulation) so that the channel can sense the specific changes in [Ca ²⁺ ] resulting after an action potential.

Significance: The human ERG (hERG) voltage-gated K ⁺ channel has an important role in heart rhythm, and channel malfunction can result in arrhythmias and sudden death. The Per-Arnt-Sim (PAS) and cyclic nucleotide binding homology (CNBh) domains in hERG influence some of the channel’s unique functional properties. However, the role of these domains is not completely understood. We use a conformation-sensitive antibody to show that the PAS/CNBh assembly is an active participant in the mechanism of channel gating: the assembly is destabilized when the channel gate opens and stabilized when the gate is closed. This finding adds to the understanding of hERG and provides avenues to correct channel function in disease.