Biology subjects

Saadatmand, A.

Publications and source records attributed to Saadatmand, A..

3 recordsLinked to original sources

bioRxiv2025

CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This "fuel switch" promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and {beta}-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2-NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF.

physiology↗

bioRxiv2025

Somatic Hdac4-902fs mutations lead to loss of HDAC4 function through nonsense-mediated mRNA degradation

Histone deacetylases (HDACs) are essential chromatin regulators and are involved in the regulation of gene expression by removing acetyl groups from histone and non-histone proteins. Histone deacetylase 4 (HDAC4) is known to regulate the process of endochondral ossification in mice by non-enzymatic repression of the activity of the RUNX2 transcription factor (TF) and to control cardiac metabolism in physiological stress situations. In this study, we examined the function of somatic HDAC4-902 frameshift (fs) mutations that are frequently observed in gastric and colon adenocarcinoma patients. Whether these mutations lead to a gain- or a loss-of-function is currently unknown. Here we generated a murine model bearing a germline HDAC4-methionine (M) amino acid (AA) 902-to-histidine (H) frameshift (M902Hfs) mutation. HDAC4-M902Hfs mice phenocopied HDAC4 null mice and present with premature ossification and early postnatal death. Mechanistically, we found that the HDAC4-M902Hfs mutation induced nonsense-mediated mRNA decay, resulting in loss of HDAC4 protein. This loss-of-function (LOF) effect was further supported by increased mRNA and protein expression of runt-related transcription factor-2 (RUNX2) and reduced class IIa HDAC enzymatic activity, indicating that HDAC4 contributes significantly to endogenous class IIa HDAC activity. Patient-derived data suggest that the HDAC4-902fs mutation is associated with reduced mRNA expression of HDAC4. In conclusion, our study identify that HDAC4-902fs mutation is a loss-of-function mutation, but raises the new question whether the loss of non-enzymatic mechanisms or the reduction in class IIa HDAC activity contributes to tumor progression.

cancer biology↗

bioRxiv2020

Phosphorylation of Threonine 107 by Calcium/Calmodulin dependent Kinase II δ Regulates the Detoxification Efficiency and Proteomic Integrity of Glyoxalase 1

The glyoxalase system is a ubiquitously expressed enzyme system with narrow substrate specificity and is responsible for the detoxification of harmful methylglyoxal (MG), a spontaneous by-product of energy metabolism. Glyoxalase 1 (Glo1) is the first and therefore rate limiting enzyme of this protective system. In this study we were able to show that a phosphorylation of threonine-107 in the Glo1 protein, mediated by Ca2+/Calmodulin-dependent Kinase II delta (CamKII{delta}), is associated with elevated catalytic efficiency of Glo1. In fact, Michaelis-Menten kinetics of Glo1 mutants revealed that a permanent phosphorylation of Glo1 was associated with increased Vmax (1.23 {micro}mol/min/mg) and decreased Km (0.19 mM HTA), whereas the non-phosphorylatable Glo1 showed significantly lower Vmax (0.66 {micro}mol/min/mg) and increased Km (0.31 mM HTA). This was also confirmed with human recombinant Glo1 (Vmax (Glo1phos) = 999 {micro}mol/min/mg; Km (Glo1phos) = 0.09 mM HTA vs. Vmax (Glo1red) = 497 {micro}mol/min/mg; Km (Glo1red) = 0.12 mM HTA). Additionally, proteasomal degradation of non-phosphorylated Glo1 via ubiquitination occurred more rapidly as compared to native Glo1. The absence of the responsible kinase CamKII{delta} was associated with poor MG detoxification capacity and decreased protein content of Glo1 in a murine CamKII{delta} knock-out model. Furthermore, this regulatory mechanism is also related to an altered Glo1 status in cancer, diabetes and during aging. In summary, phosphorylation of threonine-107 in the Glo1 protein by CamKII{delta} is a quick and precise mechanism regulating Glo1 activity.

molecular biology↗