In Person Lecture: Novel Iron Sensing Mechanisms and Role of Hexokinase Mitochondrial Binding in the Development of HFpEF
Hossein Ardehali, M.D., Ph.D.
Thomas D. Spies Professor of Cardiac Metabolism
Director, Center for Molecular Cardiology
Feinberg School of Medicine
Northwestern University
Timothy A. Johnson Medical Scholar Lecture: Novel Iron Sensing Mechanisms and Role of Hexokinase Mitochondrial Binding in the Development of HFpEF
Date: Sept. 22, 2023
Time: 1 to 2 p.m.
Archived video
About this Seminar
In the first part of his talk, Dr. Ardehali will talk about novel mechanisms of iron sensing. All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, Dr. Ardehali and his lab report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, they identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
In the second part, Dr. Ardehali will talk about mechanism of heart failure with preserved ejection fraction (HFpEF) , which is a common cause of morbidity and mortality worldwide, but its underlying pathophysiology is not well-understood and treatment options are limited. Hexokinase-1 (HK1) mitochondrial-binding and protein O-GlcNAcylation are both altered in conditions with risk factors for HFpEF. Here Dr. Ardehali and his team report a novel mouse model of HFpEF and show that HK1 mitochondrial-binding in endothelial cells (EC) is critical for the development of HFpEF. The researchers demonstrate increased mitochondrial dislocation of HK1 in ECs from HFpEF mice. Mice with deletion of the mitochondrial-binding-domain of HK1 spontaneously develop HFpEF, and their ECs display impaired angiogenic potential. Mitochondrial-bound HK1 associates with dolichyl-diphosphooligosaccharide-protein-glycosyltransferase (DDOST) and its mitochondrial dislocation decreases protein N-glycosylation. Pharmacological inhibition of OGT or EC-specific overexpression of O-GlcNAcase reverses angiogenic defects in ECs and the HFpEF phenotype, indicating that increased protein O-GlcNAcylation is responsible for the development of HFpEF. The lab’s study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation in ECs and provides a potential new therapy for this disorder.
Additional Details
This is a free event hosted by the Fralin Biomedical Research Institute and the Virginia Tech Carilion School of Medicine. The Timothy A. Johnson Medical Scholar Lecture Series hosts clinician scientists who are exploring frontiers of medicine. These lectures are principally intended for Virginia Tech Carilion School of Medicine students and Virginia Tech students in the Translational Biology, Medicine, and Health graduate program. Virginia Tech and Carilion Clinic faculty, staff, and students may also attend.
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