The Jhun laboratory aims to identify the molecular mechanisms involved in the development of cardiovascular diseases. We are particularly interested in mitochondrial signaling pathways that control mitochondrial fission, fusion, and ion transport during physiological conditions, and how alterations in these processes influence mitochondrial and cellular function under pathological conditions. To this end, we utilize a wide range of techniques from genetic, biochemical, molecular/cell biological, and physiological approaches to in vivo animal models of cardiovascular diseases. Elucidation of these regulatory mechanisms will facilitate the design of novel therapeutic strategies for the management of cardiovascular diseases.
"Role of PKD and its substrates in mitochondria in cardiac pathology"
Protein kinase D (PKD) is a serine/threonine protein kinase activated by cellular oxidative stress signaling including Gq-protein coupled receptor stimulation. Although the pathophysiological role of PKD in cardiac myocytes in left ventricles has been extensively studied in both cellular and in vivo genetic models, much less is known about its function in cardiac fibroblasts.
We are currently investigating the role of PKD-mediated mitochondrial signaling in cardiac fibroblasts under pathological conditions. Our preliminary data suggest that PKD activation and its novel substrate phosphorylation in mitochondria are critical factors in apoptotic resistance and cell proliferation in right ventricular (RV) fibroblasts, resulting in RV fibrosis and dysfunction during pulmonary arterial hypertension (PAH). Based on these data, we are developing a novel genetic tool for mitochondrial PKD inhibition and testing its efficacy in a preclinical rat model of PAH. This study will provide new insights into the molecular mechanisms underlying PAH-induced RV fibrosis and failure. Moreover, the outcome of this project will lead to the design of a novel strategy for the development of effective anti-fibrotic therapy in RV failure. (Partially supported by American Heart Association Career Development Award #18CDA34110091, PI: Jhun).
"Regulation and Function of Mitochondrial Ion Channels/Transporters in the Cardiovascular System"
In collaboration with internal and external investigators, the Jhun laboratory is investigating the regulatory mechanisms and functional roles of various ion channels and transporters in cell survival and death in the cardiovascular system. These include mitochondrial calcium uniporter (NIH/NHLBI R01HL136757, PI: O-Uchi & Co-I: Jhun and University of Minnesota IEM Group Program Grant, MPIs: Talkachova, O-Uchi, Dudley & Co-I: Jhun) and calcium-activated chloride channel Anoctamin 1 (NIH/NHLBI R01HL148727 PI: Choudhary & Co-I: Jhun).
Principal Investigator: Bong Sook Jhun, PhD, FCVS
Assistant Professor of Medicine
Lillehei Heart Institute
Department of Medicine
University of Minnesota
Michael W. Cypress, PhD
Lab Manager for Jhun and O-Uchi labs
Bridget Nieto, BS
Animal Research Specialist for Jhun and O-Uchi labs
Maria Landherr, BS
Undergraduate Research Associate
Neeta Adhikari, PhD
Jordan Schlichting, BS
Research Technician for Jhun and O-Uchi labs
Xiaoxu Zhou, MD, PhD
Assistant Professor of Medicine
Full list of publications at Experts@Minnesota
1. Adaniya SM, O-Uchi J, Cypress MW, Kusakari Y, Jhun BS#: Posttranslational Modifications of Mitochondrial Fission and Fusion Proteins in Cardiac Physiology and Pathophysiology. Am J Physiol Cell Physiol. 2019, 316(5): C583-C604. PMID: 30758993 (#Corresponding author)
2. Jhun BS#, O-Uchi J#, Adaniya SM, Cypress MW, Yoon Y. Adrenergic Regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology. Antioxidants. 2018, 7(12): E195, PMID: 30567380 (#Corresponding author)
3. Jhun BS#, O-Uchi J#, Adaniya SM, Mancini TJ, Cao JL, King ME, Landi AK, Ma H, Shin M, Yang D, Xu X, Yoon Y, Choudhary G, Clements RT, Mende U, Sheu SS#: Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes. J. Physiol. 2018, 596(5):827-855. PMCID: PMC5830422 (#Corresponding author)
4. Jhun BS*, Mishra J*, Hurst S, O-Uchi J, Csordás G, Sheu SS. The Mitochondrial Ca2+ uniporter: Structure, Function and Pharmacology. Handb Exp Pharmacol. 2017, 240:129-156. PMCID: PMC5554456 (*Equal contribution)
5. Jhun BS*, Mishra J, Monaco S, Fu D, Jiang W, Sheu SS, O-Uchi J: The mitochondrial Ca2+ uniporter: Regulation by auxiliary subunits and signal transduction pathways. Am J Physiol Cell Physiol. 2016, 311(1):C67-80. PMCID: PMC4967134. (*Equal contribution)
6. Jhun BS*, O-Uchi Jin*, Xu S, Hurst S, Raffaello A, Liu X, Yi B, Zhang H, Gross P, Mishra J, Ainbinder A, Kettlewell S, Smith GL, Dirksen RT, Wang W, Rizzuto R, Sheu SS: Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter. Antioxid Redox Signal. 2014, 21(6):863-79. PMCID: PMC4116095 (*Equal contribution)
7. O-Uchi J, Jhun BS, Hurst S, Bisetto S, Gross P, Chen M, Kettlewell S, Park J, Oyamada H, Smith GL, Murayama T, Sheu SS: Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts. Am J Physiol Heart Circ Physiol. 2013, 305(12):H1736-51. PMCID: PMC3882548
8. Jhun BS, Lee H, Jin ZG, Yoon Y: Glucose stimulation induces dynamic change of mitochondrial morphology to promote insulin secretion in the insulinoma cell line INS-1E. PLoS One. 2013, 8(4):e60810. PMCID: PMC3614983
9. Galloway CA, Lee H, Nejjar S, Jhun BS, Yu T, Hsu W, Yoon Y: Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress in mice. Diabetes. 2012, 61(8): 2093-2104. PMCID: PMC3402299
10. Jhun BS*, O-Uchi Jin*, Wang W, Ha CH, Zhao J, Kim JY, Wong C, Dirksen RT, Lopes CM, Jin ZG: Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca2+ channels through PKD1. Circ Res. 2012, 110: 59-70. PMCID: PMC4232192 (*Equal Contribution)
11. Yoon Y, Galloway CA, Jhun BS, Yu T: Mitochondrial Dynamics in Diabetes. Antioxid Redox Signal. 2011, 14(3): 439-457. PMCID: PMC3025181
12. Yu T, Jhun BS, Yoon Y: High-Glucose Stimulation Increases Reactive Oxygen Species Production Through the Calcium and Mitogen-Activated Protein Kinase-Mediated Activation of Mitochondrial Fission. Antioxid Redox Signal. 2011, 14(3): 425-437. PMCID: PMC3025178