Gwangbeom Heo

All Publications

• ATP Mediates Pyroptosis in the Intestinal Mucosal System During Colitis JOURNAL OF CELLULAR PHYSIOLOGY Jeong, S., Park, S., Lee, D., Heo, G., Lee, Y., Rhee, S., Im, E. 2025; 240 (7): e70071

  Abstract

  Damage-associated molecular patterns (DAMPs) are molecules released from damaged or dying cells that contribute to inflammation and cell death. Extracellular ATP, a type of DAMP, has been studied primarily in the context of pyroptosis in monocytes. This study aimed to investigate the role of ATP as a DAMP in mediating pyroptosis within the intestinal mucosal system. Colitis was induced in mice by administering dextran sodium sulfate, followed by analysis of ATP levels and with the expression of pyroptosis-related proteins. Colonic epithelial cells were treated with ATP to assess cell death and pyroptosis levels. Mice with colitis exhibited elevated ATP levels in the colon and serum. Additionally, the expression of pyroptosis-related mediators was significantly upregulated in the colons of these mice. In vitro, ATP treatment increased cell death and mitochondrial dysfunction in colonic epithelial cells. ATP also enhanced inflammatory and pyroptosis responses in these cells, while the expression of apoptosis mediator proteins remained unchanged. Notably, ATP did not further enhance flagellin-induced inflammation. These findings demonstrate that ATP levels are elevated in colitis and that ATP functions as a DAMP to induce pyroptosis in intestinal epithelial cells. This study also highlights a self-propagating cycle where ATP released during pyroptosis triggers further pyroptosis in adjacent cells, exacerbating the condition. Importantly, this study extends our understanding of ATP-mediated pyroptosis to the context of the intestinal mucosal system.

  View details for DOI 10.1002/jcp.70071

  View details for Web of Science ID 001541551100006

  View details for PubMedID 40686264

  View details for PubMedCentralID PMC12278297

• A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress. Nature communications Pokhrel, S., Heo, G., Mathews, I., Yokoi, S., Matsui, T., Mitsutake, A., Wakatsuki, S., Mochly-Rosen, D. 2025; 16 (1): 4187

  Abstract

  Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

  View details for DOI 10.1038/s41467-025-59434-6

  View details for PubMedID 40328741

  View details for PubMedCentralID PMC12056058

• Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction. Nature communications Rios, L., Pokhrel, S., Li, S. J., Heo, G., Haileselassie, B., Mochly-Rosen, D. 2023; 14 (1): 4356

  Abstract

  The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.

  View details for DOI 10.1038/s41467-023-40043-0

  View details for PubMedID 37468472

  View details for PubMedCentralID PMC10356917

• Atractylodin Ameliorates Colitis via PPARα Agonism INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Heo, G., Kim, Y., Kim, E., Park, S., Rhee, S., Jung, J. H. H., Im, E. 2023; 24 (1)

  Abstract

  Atractylodin is a major compound in the rhizome of Atractylodes lancea, an oriental herbal medicine used for the treatment of gastrointestinal diseases, including dyspepsia, nausea, and diarrhea. Recent studies have shown that atractylodin exerts anti-inflammatory effects in various inflammatory diseases. Herein, we investigated the anti-colitis effects of atractylodin and its molecular targets. We determined the non-cytotoxic concentration of atractylodin (50 μM) using a cell proliferation assay in colonic epithelial cells. We found that pretreatment with atractylodin significantly inhibits tumor necrosis factor-α-induced phosphorylation of nuclear factor-κ-light-chain-enhancer of activated B in HCT116 cells. Through docking simulation analysis, luciferase assays, and in vitro binding assays, we found that atractylodin has an affinity for peroxisome proliferator-activated receptor alpha (PPARα). Daily administration of atractylodin (40 mg/kg) increased the survival rate of mice in a dextran sodium sulfate-induced colitis mouse model. Thus, atractylodin can be a good strategy for colitis therapy through inducing PPARα-dependent pathways.

  View details for DOI 10.3390/ijms24010802

  View details for Web of Science ID 000909023700001

  View details for PubMedID 36614242

  View details for PubMedCentralID PMC9821687