O-Uchi Lab

Advancing therapies for preventing sudden cardiac death by COVID-19 viroporins in patients with pre-existing hypertension

COVID-19 caused by the SARS-CoV-2 is an ongoing global health emergency. In this project, we will address 1) why COVID-19 patients with pre-existing cardiovascular disease (CVD) have a higher risk for severe illness and death, 2) what are the specific molecular mechanisms to link COVID-19 and the heart, and 3) how we can acquire immediate and actionable outcomes to reduce this risk using available resources and approaches. The major objective is to test our hypothesis that expression of viral ion channels (i.e. “viroporins”) from SARS-CoV-2 in the heart increases the risk of sudden cardiac death (SCD) and cardiac damage in COVID-19 patients with pre-existing CVD, especially with hypertension (HTN), which is reported as a most frequent cardiovascular risk factor in COVID-19 cohorts. Moreover, we will test the efficacy of clinically approved magnesium (Mg) supplementation (Supported by OACA COVID-19 Response Grant, PI: O-Uchi, Co-PI: Talkachova) and a clinically approved potassium channel blocker 4-Aminopyridine (Supported by IEM COVID-19 Response Grant, PI: O-Uchi) for preventing SCD in COVID-19 with pre-existing HTN.

Regulation of mitochondrial calcium uniporter in the cardiomyocytes

Mitochondrial Ca²⁺ homeostasis determines cardiac functions, including energy metabolism, reactive oxygen species (ROS) generation, spatiotemporal dynamics of Ca²⁺ signaling, cell growth/development and death. Especially mitochondrial Ca²⁺ uptake mechanism across the inner membrane (IMM) is important for Ca²⁺-dependent regulation of ATP synthesis. This project is to elucidate the role of a newly identified short transcript variant of the mitochondrial Ca²⁺ uniporter (MCU-S) in the regulation of cellular metabolism, mitochondrial Ca²⁺ handling, ROS production and apoptotic death in the cardiomyocytes. (Supported by NIH/NHLBI R01HL136757, PI: O-Uchi).

Post-translational modification of cardiac mitochondrial calcium uniporter

This project is to identify the signaling pathways that control mitochondrial Ca²⁺ entry via the post-translational modification of MCU, especially focusing on tyrosine phosphorylation of MCU by mitochondria-localized proline-rich tyrosine kinase 2 (Pyk2). In addition, this study will establish the inhibition of MCU tyrosine phosphorylation as a novel therapeutic target for prevent mitochondrial Ca²⁺ overload, oxidative stress, and mitochondrial injury (Supported by APS Shih-Chun Wang Young Investigator Award, PI: O-Uchi).

Role of mitochondrial calcium uniporter in the cardiac fibroblasts

This project is to elucidate the role of MCU in the regulation of cardiac fibroblast activation, cardiac fibrosis, and arrhythmia generation after myocardial infarction. (Supported by IEM Group Program Grant, M-Pis: Talkachova, O-Uchi, Dudley)

Role of mitochondrial RyR1 in cardiac arrhythmia and sudden cardiac death

This project investigates the detailed mechanism underlying the generation of cardiac arrhythmias and sudden cardiac death in malignant hyperthermia (MH) using knock-in mice carrying a RyR1 mutation Y522S (YS mice) found in the human MH family. (Supported by AHA 16SDG27260248, PI: O-Uchi)

Mitochondrial ion channels/transporters in cell survival and death

In addition to mitochondrial Ca²⁺ uptake mechanism, O-Uchi lab is investigating the roles of various ion channels/transporters on ROS generations, and cell survival and death though the national and international collaborations. These includes BK channel (NIH/NHLBI R01HL135236 PI: Clements, Subaward PI: O-Uchi), SK channel (NIH/NHLBI R01HL142588 PI: Terentyev (PI), Subaward PI: O-Uchi), electron transport chain (VA BLR&D ULM-004-18S MERIT REVIEW PI: Choudhary, Co-I: O-Uchi), and Cl- channel (NIH/NHLBI R01HL148727 PI: Choudhary, Subaward PI: O-Uchi).

Full list of publications at Experts@Minnesota.

1. O-Uchi J*, Adaniya SM*, Cypress M, Jhun BS. Post-translational modifications of mitochondrial fission and fusion proteins: implications for physiology and cardiac disease. Am. J. Physiol Cell Physiol. 2019 (*Equal contribution) PMID: 30758993
2. Cao JL, Adaniya SM, Cypress, M, Suzuki Y, Kusakari Y, Jhun BS, O-Uchi J*. Mitochondrial Calcium Handing in Cardiac Muscles. Arch. Biochem. Biophys., 663: 276-287, 2019. PMID: 30684463 *Corresponding author.
3. O-Uchi J*#, Jhun BS*#, Adaniya SM, Cypress M, Yoon Y. Adrenergic regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology. Antioxidants (Basel), 18;7(12). pii: E195, 2018. (*Equal contribution). PMID: 30567380 #Corresponding authors.
4. O-Uchi J*#, Jhun BS*#, Adaniya SM, Mancini TJ, Landi AK, Cao JL, 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. 596(5):827-855, 2018. PMID: 29313986 (#Equal contribution) *Corresponding authors.
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. 311(1):C67-80, 2016. PMID: 27122161 *Corresponding author
6. O-Uchi J, Rice JJ, Ruwald MH, Parks XX, Ronzier E, Moss AJ, Zareba W, Lopes CM. Impaired IKs channel activation by Ca2+-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1. J Mol Cell Cardiol. 79:203-211, 2015.
7. O-Uchi J*, Jhun BS, 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. 21(6):863-79, 2014. PMID:24800979. * Corresponding author.
8. O-Uchi, J*, Jhun BS*, Wang W, Ha CH, Zhao J, Kim JY, Wong C, Dirksen RT, Lopes CM, Jin ZG. (*Equal contribution). Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca2+ channels through PKD1. Circ Res. 110(1):59-70, 2012. PMID: 22076634
9. O-Uchi J*, Barsheshet A*, Goldenberg I *, Moss AJ, Jons C, Shimizu W, Wilde AA, McNitt S, Zareba W, Robinson JL, Ackerman MJ, Cypress M, Gray DA, Hofmann, Kanters JK, Kaufman ES, Platonov PG, Qi M, Towbin JA, Vincent, GM, Lopes CM (*Equal contribution). Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. Circulation. 125(16):1988-96, 2012. PMID: 22456477
10. Hoefen R, Reumann M, Goldenberg, I, Moss AJ, O-Uchi J, Gu Y, McNitt S, Zareba W, Jons C, Kanters J, Platonov P, Shimizu W, Wilde AA, Rice JJ. In Silico Cardiac Risk Assessment of Long QT type 1 patients: clinical predictability of cardiac models. J Am Coll Cardiol. 60(21):2182-91, 2012. PMID: 23153844
11. O-Uchi, J*, Jons, C*, Moss, AJ, Reumann, M, Rice, JJ., Goldenberg, I, Zareba, W, Wilde, AA, Shimizu, W, Kanters, JK, McNitt, S, Hofman, N, Robinson, JL, Lopes, CMB. (*Equal contribution).Use of Mutant-Specific Ion Channel Characteristics for Risk Stratification of Long QT Syndrome Patients. Science Translational Medicine. (2011)3(76):76ra28, 2011. [Cover Image] PMID: 21451124
12. O-Uchi J*, Sasaki H, Morimoto S, Kusakari Y, Shinji H, Obata T, Hongo K, Komukai K, Kurihara S. Interaction of a1-adrenoceptor subtypes with different G proteins induces opposite effects on cardiac L-type Ca2+ channel. Circ Res. 102:1378-1388, 2008.PMID: 18467629 *Corresponding author.
13. O-Uchi J*, Komukai K, Kusakari Y, Obata T, Hongo K, Sasaki H, Kurihara S. alpha1-Adrenoceptor stimulation potentiates L-type Ca2+ current through Ca2+/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes. Proc Natl Acad Sci U S A. 102(26):9400-9405, 2005. PMID: 15964981 *Corresponding author

Full list of publications at Experts@Minnesota.

Principal Investigator:
Jin O-Uchi, MD, PhD

Assistant Professor of Medicine
Lillehei Heart Institute
Department of Medicine, Cardiovascular Division
University of Minnesota
jouchi@umn.edu

Xiaoxu Zhou, MD, PhD

Assistant Professor of Medicine
zhou1304@umn.edu

Iuliia Polina, PhD

Senior Scientist
polin066@umn.edu

Michael W Cypress, PhD

Lab Manager for O-Uchi and Jhun labs
mcypress@umn.edu

Bridget Nieto, BS

Animal Research Specialist for O-Uchi and Jhun labs
mell0112@umn.edu

Isabel Chaput

Undergraduate Research Associate
chapu023@umn.edu

Maria Landherr

Undergraduate Research Associate
2021 LHI Summer Scholar
landh014@umn.edu

Former Members

Neeta Adhikari, PhD

Senior Scientist
adhik001@umn.edu

Gayathri Dileepan

Undergraduate Honor Thesis Candidate
dilee003@umn.edu

Kamelia Drenkova

Undergraduate Research Associate
drenk002@umn.edu

Seonmi Park, BA

Undergraduate Volunteer
park2234@umn.edu

Jae Hwi Sung, MS

Graduate Student in Integrative Biology and Physiology
sung0031@umn.edu

Yuta Suzuki, MD, PhD

Post-doctoral Research Associate
suzukiy@umn.edu

Jordan Schlichting, BS

Research Technician for O-Uchi and Jhun labs
schli364@umn.edu

Hannah Thompson

Undergraduate Volunteer
thom6194@umn.edu

Dora Azeudong Tsobze

APS Hearst Undergraduate Summer Research Fellow
tsobz001@umn.edu