Biology subjects

Lee, J.-G.

Publications and source records attributed to Lee, J.-G..

3 recordsLinked to original sources

bioRxiv2025

Isoflurane and Surgical Stress Disrupt Fatty Acid and Carbon Metabolism Leading to Cardiomyopathy

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis of these effects remains poorly understood. To define age-dependent cardiac transcriptional responses to isoflurane exposure and operative (ISO/OP) stress, we analyzed gene expression profiles across young adult (3m), late middle-aged (17m), and geriatric mice (27m) following short-term 2 h ISO/OP exposure. At 24 h after cessation, all age groups exhibited distinct cardiac transcriptional signatures separating ISO/OP from sham controls. In young adult hearts, transcriptional alterations 24 hours after cessation of ISO/OP were characterized by dysregulation of small molecule catabolic processes, fatty acid metabolism, disruptions to protein processing in endoplasmic reticulum and cytoskeletal organization. Late middle-aged mice displayed amplified perturbations in lipid metabolism alongside suppression of muscle system and calcium signaling pathways, while old mice showed robust activation of PPAR and AMPK signaling and downregulation of genes governing contractility and morphogenesis. In contrast, geriatric mice showed upregulation of fatty acid metabolic pathways, robust activation of PPAR and AMPK signaling, coupled with suppression of muscle differentiation and actin organization following ISO exposure, indicating a maladaptive metabolic reprogramming. Overlapping DEGs across all age groups converged on pathways regulating oxidative stress, Ca2+ handling, hypertrophy, and energy metabolism, suggesting a conserved but age-intensified cardiac stress response. Longitudinal profiling in aged mice revealed persistent transcriptomic remodeling five weeks after stress. Crucially, this remodeling was observed even after ISO exposure alone, indicating that general anesthesia is a primary driver of this long-term effect. This persistent signature was marked by mitochondrial dysfunction and dysregulation of genes associated with diabetic cardiomyopathy, extracellular matrix integrity, and neurodegenerative signaling. Together, these findings identify isoflurane exposure as a potent inducer of persistent, age-dependent metabolic and structural reprogramming in the heart, implicating impaired lipid utilization and mitochondrial homeostasis as central mechanisms linking the perioperative period, and specifically anesthetic exposure, to long-term cardiovascular vulnerability.

pharmacology and toxicology↗

bioRxiv2019

Intramembrane protease RHBDL4 interacts with erlin complex to target unstable soluble proteins for degradation

Protein degradation is fundamentally important to ensure cell homeostasis. In the endoplasmic reticulum (ER), the ER-associated degradation (ERAD) pathway targets incorrectly folded and unassembled proteins into the cytoplasm for turnover by the proteasome. In contrast, lysosomal degradation serves as a failsafe mechanism for removing proteins that resist ERAD by forming aggregates. Previously, we showed that the ER- resident rhomboid protease RHBDL4, together with p97, mediates membrane protein degradation. However, whether RHBDL4 acts in concert with additional ERAD components is unclear, and its full substrate spectrum remains to be defined. Here, we show that besides membrane proteins, RHBDL4 cleaves aggregation-prone luminal ERAD substrates. Because RHBDL4 with mutations in the rhomboid domain leads to stabilization of substrates at the cytoplasmic side, we hypothesize that analogue to the homologue ERAD factor derlin, RHBDL4 is directly involved in substrate retrotranslocation. RHBDL4s interaction with the erlin ERAD complex and reciprocal interaction of rhomboid substrates with erlins suggest that RHBDL4 and erlins form a complex that clips substrates and thereby rescues aggregation-prone peptides in the ER lumen from terminal aggregation.

cell biology↗

bioRxiv2018

Vascular defects of DYRK1A knockouts are ameliorated by modulating calcium signaling in zebrafish

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors and vascular anomalies in DS patients suggests a role of DYRK1A in angiogenesis, but in vivo evidence is lacking. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in the cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that dyrk1aa plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases.

developmental biology↗