Jin O-Uchi

University of Minnesota Twin Cities | UMN · Division of Cardiology

Aims: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phospho...

Inherited long QT syndrome (LQTS) is caused by mutations in ion channels that delay cardiac repolarization, increasing the risk of sudden death from ventricular arrhythmias. Currently, the risk of sudden death in individuals with LQTS is estimated from clinical parameters such as age, gender, and the QT interval, measured from the electrocardiogram...

The Rad-Gem/Kir-related family (RGKs) consists of small GTP-binding proteins that strongly inhibit the activity of voltage-gated calcium channels. Among RGKs, Rem1 is strongly and specifically expressed in cardiac tissue. However, the physiological role and regulation of RGKs, and Rem1 in particular, are largely unknown. ObjecTIVE: To determine if...

β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location. The study sample comprised 860 patients with genetically confirmed mutations in the...

Key points: Abnormal mitochondrial morphology and function in cardiomyocytes are frequently observed under persistent Gq protein-coupled receptor (Gq PCR) stimulation. Cardiac signalling mechanisms for regulating mitochondrial morphology and function under pathophysiological conditions in the heart are still poorly understood. We demonstrate that...

Background Mutations in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enhance its pathogenicity by affecting its transmissibility, disease severity, and overall mortality in human populations. In addition to mutations within the coding region of SARS-CoV-2 structural proteins, there have been reports of mutati...

Cardiac fibroblasts (CFs) are an attractive target for reducing pathological cardiac remodeling, and understanding the underlying mechanisms of these processes is the key to develop successful therapies for treating the pressure-overloaded heart. CF-specific knockout (KO) mouse lines with a Cre recombinase under the control of human TCF21 (hTCF21)...

MCU is widely recognized as a responsible gene for encoding a pore-forming subunit of highly mitochondrial-specific and Ca2+-selective channel, mitochondrial Ca2+ uniporter complex (mtCUC). Here, we report a novel short variant derived from the MCU gene (termed MCU-S) which lacks mitochondria-targeted sequence and forms a Ca2+-permeable channel out...

Introduction: A mitochondrial fusion protein, Mitofusin 2 (Mfn2) serves as one of the major components for tethering the mitochondria and endoplasmic reticulum (ER), which regulates the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Several post-translational modifications (PTMs) of Mfn2 have been identified...

Introduction: Mechanical stress (e.g., pressure overload), cytokines, growth factors, and neurohumoral mediators stimulate cardiac fibroblast (CF) activation, which promotes extracellular matrix (ECM) protein synthesis leading to cardiac fibrosis and diastolic dysfunction. Therefore, CFs are an attractive target for reducing pathological cardiac re...

Introduction: Growing evidence suggests a link between right ventricular (RV) fibrosis, poor function of the pressure-overloaded RV, and mortality in pulmonary arterial hypertension (PAH). However, there are no currently available therapies that specifically target RV fibrosis. Using RV tissues from a preclinical rat PAH model, we previously report...

Introduction: Discovery of the molecular identity of the mitochondrial Ca ²⁺ (mtCa ²⁺ ) uniporter complex (mtCUC) provides rapid progress in characterizing mtCa ²⁺ handling and its roles in regulating cellular functions. MCU, a pore-forming subunit of mtCUC, which resides at the inner mitochondrial membrane, forms the major mtCa ²⁺ influx pathway....

Introduction: Direct infection and viral protein expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the respiratory system, and other organs including the heart, contribute to multi-organ dysfunction during COVID-19. We previously showed that the protein encoded by the open reading frame 3a (ORF3a) gene of SARS-CoV-2, whi...

Intermittent fasting (IF) extends life span via pleotropic mechanisms, but one important molecular mediator is adenosine monophosphate-activated protein kinase (AMPK). AMPK enhances lipid metabolism and modulates microtubule dynamics. Dysregulation of these molecular pathways causes right ventricular (RV) failure in patients with pulmonary arterial...

Introduction: Cardiac fibrosis, characterized by wall stiffening, reduced contractility, and impaired overall heart performance, is a self-reinforcing process in response to injury (e.g., myocardial infarction) and pressure overload (e.g., systemic hypertension and pulmonary arterial hypertension [PAH]). The severity of cardiac fibrosis is associa...

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the respiratory system. However, direct SARS-CoV-2 infection and viral protein expression have also been reported in other organs, which potentially contributes to multi-organ dysfunction and increased mortality in COVID-19. Since the original Wuhan-type g...

Introduction: The Ca2+ -activated Cl- channel Anoctamin-1 (Ano1) regulates multiple cell functions including cell proliferation, survival, and migration. We previously reported that overexpression of Ano1 is associated with hyperproliferation of pulmonary artery endothelial cells isolated from patients with idiopathic pulmonary arterial hypertensi...

Contact sites between the mitochondria and endoplasmic reticulum (ER) are irregulates the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Mitofusin 2 (Mfn2) has been shown as one of the major components tethering these two organelles. Several post-translational modifications (PTMs) of Mfn2 have been identified...

Introduction: We have described previously an arrhythmic mechanism in nonischemic heart failure (HF) involving an increased mitochondrial Ca ²⁺ uptake that results in QT prolongation and lethal arrhythmias during cardiomyopathy. This arrhythmic mechanism is associated with mitochondrial Ca ²⁺ uniporter (MCU) tyrosine phosphorylation (p-Tyr). Hypoth...

Introduction: Hypomagnesemia (HypoMg) induces mitochondrial dysfunction accompanied by disturbed Mg homeostasis in mouse hearts. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function located in the plasma membrane. Its upregulation has been observed in HypoMg. We investigated the...

Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, although there is no specific treatment for HFpEF yet because of poor understanding of the underlying pathophysiology. Our previous studies show that hypomagnesemia contributes to diastolic dysfunction and HFpEF by regulation of mitochondrial funct...

Right ventricular (RV) fibrosis is a key feature of maladaptive RV hypertrophy and dysfunction and is associated with poor outcomes in pulmonary hypertension (PH). However, mechanisms and therapeutic strategies to mitigate RV fibrosis remain unrealized. Previously, we identified that cardiac fibroblast α7 nicotinic acetylcholine receptor (α7 nAChR)...

Background Premature atrial contractions (PACs) are associated with increased risk of atrial fibrillation (AF) and ischemic stroke. Although lifestyle and risk factor modification reduces AF incidence, their relationship to PACs frequency is unclear. We assessed the association of Life's Simple 7 (LS7) and individual LS7 factors in midlife with PAC...

Introduction: COVID-19 patients with pre-existing cardiovascular diseases (CVDs) have a higher risk for severe illness, cardiac damage, and death. Therefore, strategies for cardiovascular protection in COVID-19 are urgently needed until a reliable and effective treatment for COVID-19 (e.g., vaccine) is established. Because angiotensin-converting en...

Introduction: We have described previously an arrhythmic mechanism in nonischemic heart failure (NI-HF) involving an increased mitochondrial Ca ²⁺ uptake that results in QT prolongation and lethal arrhythmias. This arrhythmic mechanism is associated with mitochondrial Ca ²⁺ uniporter (MCU) tyrosine phosphorylation (p-Tyr). Hypothesis: Here, we dete...

Introduction Contact sites between the endoplasmic reticulum (ER) and mitochondria (i.e., mitochondria‐associated membranes: MAMs) have important roles for the exchange of lipids, Ca ²⁺ , and reactive oxygen species (ROS), and greatly influence mitochondrial bioenergetics and cell fate. Mitofusin 2 (Mfn2), a mitochondrial fusion protein, is critica...

Introduction Mitochondrial Ca ²⁺ (mtCa ²⁺ ) uptake via a main mtCa ²⁺ channel, mtCa ²⁺ uniporter (MCU), mediates cell survival and death via its contribution of mitochondrial ATP synthesis and apoptotic signaling activation, respectively. Our group previously showed that G q protein–coupled receptor (G q PCR) stimulation promotes activation of a ty...

Activation of a Ca ²⁺ ‐activated chloride channel, anoctamin‐1 (Ano1), is associated with enhanced cell proliferation in multiple cell types, such as endothelial cells (ECs). Recent proteomics studies indicate that Ano1 may interact with mitochondrial proteins in addition to plasma membrane (PM)‐localized proteins. However, the expression levels of...

Background Mitochondrial Ca ²⁺ (mtCa ²⁺ ) uptake via a main mtCa ²⁺ channel, mtCa ²⁺ uniporter (MCU), is an essential element to produce ATP at the mitochondria, the form of energy indispensable for the development and survival of various cell types including in cardiomyocytes (CMs). However, the excessive amount of mtCa ²⁺ oppositely decreases ATP...

AimAging in humans is associated with a 10–40-fold greater incidence of sudden cardiac death from malignant tachyarrhythmia. We have reported that thiol oxidation of ryanodine receptors (RyR2s) by mitochondria-derived reactive oxygen species (mito-ROS) contributes to defective Ca2+ homeostasis in cardiomyocytes (CMs) from aging rabbit hearts. Howev...

Introduction: Cardiac fibrosis persists in patients with heart failure (HF) even during treatment with conventional HF therapies designed to control volume/pressure overload and restore cardiomyocyte function. This suggests a critical need to develop novel and effective anti-fibrotic therapies specifically targeting cardiac fibroblasts (CFs). CFs c...

Mitochondrial Ca ²⁺ (mtCa ²⁺ ) uptake via the mtCa ²⁺ uniporter (MCU) mediates cell survival and death. Our group previously showed that activation and mitochondrial translocation of proline‐rich tyrosine kinase 2 (Pyk2), tyrosine phosphorylation (P‐Tyr) of MCU, and enhancement of mtCa ²⁺ uptake concomitantly occur in cardiomyocytes under G q prote...

Anoctamin‐1 (Ano1) is a calcium‐activated chloride channel that can regulate cell proliferation and cell cycle in endothelial cells (ECs). According to a recent proteomics study, Ano1 interacts with mitochondrial proteins in addition to plasma‐membrane proteins. However, the expression levels of Ano1 and its functions in other cellular compartments...

Early postnatal hearts adapt to the substantial increase in systolic pressure by increasing the thickness of the ventricular wall as well as its tensile strength, which is achieved mainly by an increase in the size of cardiomyocytes (CMs) (but not the number of CMs) as well as a two‐fold increase in the number of cardiac fibroblasts (CFs). Importan...

Recent discoveries of the molecular identity of mitochondrial Ca²⁺ influx/efflux mechanisms have placed mitochondrial Ca²⁺ transport at center stage in views of cellular regulation in various cell-types/tissues. Indeed, mitochondria in cardiac muscles also possess the molecular components for efficient uptake and extraction of Ca²⁺. Over the last s...

Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab GTPase proteins, a key protein family for the regulation of protein trafficking. Rab-GTPases have been shown to be involved in the control of membrane expression level of ion channels, including one of the major cardiac repolarizing channels, IKs. Decrease...

In a physiological setting, mitochondria increase oxidative phosphorylation during periods of stress to meet increased metabolic demand. This in part is mediated via enhanced mitochondrial Ca 2+ uptake, an important regulator of cellular ATP homeostasis. In a pathophysiological setting pharmacological modulation of mitochondrial Ca 2+ uptake or ret...

Abnormal mitochondrial morphology, especially fragmented mitochondria, and mitochondrial dysfunction are hallmarks of a variety of human diseases including heart failure (HF). Although emerging evidence suggests a link between mitochondrial fragmentation and cardiac dysfunction, it is still not well described which cardiac signaling pathway regulat...

Cardiac remodeling occurs in many cardiovascular diseases. It can severely impair ventricular function and increase the risk for arrhythmias. A better understanding of cardiac signaling regulatory mechanisms is critical for development of novel and effective treatment approaches. MicroRNAs (miRNAs) are important regulators in cardiac development an...

Aging is associated with a 10–20 fold increase in the incidence of sudden cardiac death. We previously reported that post‐translational modification of ryanodine receptors (RyR2) (e.g. thiol oxidation) by mitochondria‐derived reactive oxygen species (ROS) contributes to aberrant Ca ²⁺ handling in cardiomyocytes from aging rabbit hearts (Cooper et a...

Cardiac fibroblasts (CFs) are the major cell type in addition to cardiomyocytes in the mammalian heart, and they play a vital role in regulating normal cardiac function and adaptive cardiac remodeling during adverse clinical conditions, including fibrosis. Recent studies have revealed Angiotensin II (AngII) as a one of the principal effectors for p...

Recent discovery in the molecular identity of the mitochondrial Ca ²⁺ uniporter complex (mtCUC) (a pore forming subunit MCU and regulatory subunits) provides new possibilities for applying genetic approaches to study the mitochondrial Ca ²⁺ influx mechanism and its significant impact to mitochondrial and cellular functions. Indeed, rapid progress w...

Although human pedigrees carrying the ryanodine receptor type 1 (RyR1) mutations mainly show skeletal muscle disorders including malignant hyperthermia (MH), sudden cardiac death (SCD) in these MH families in the conscious condition without anesthesia are also frequently found in the clinical case studies. However, the molecular mechanism underlyin...

Cardiac fibroblasts (CFs) are one of the major cell types in the heart in addition to cardiomyocytes, and play an important role in regulating normal cardiac function and as well as pathological cardiac remodeling (i.e. fibrosis). It has been demonstrated that the stimulation of G q ‐protein coupled receptor (G q PCR) including angiotensin II (AngI...

Malignant hyperthermia (MH) is known as a pharmacogenetic disorder of skeletal muscle that shows hypermetabolic responses to anesthetic gases. It is reported that this syndrome is associated with the ryanodine receptor type 1 (RyR1) mutations. Although clinical manifestation of MH is mainly skeletal muscle disorder under anesthesia, sudden cardiac...

Mitochondrial Ca ²⁺ (mtCa ²⁺ ) uptake via the mtCa ²⁺ uniporter (MCU) complex is a critical factor in determining cell survival or death. We previously reported that the activation of a Ca ²⁺ ‐ and reactive oxygen species (ROS)‐sensitive protein tyrosine kinase (PTK), proline‐rich tyrosine kinase 2 (Pyk2), under G q protein–coupled receptor (G q PC...

Hyperproliferative endothelial cells (ECs) play an important role in the pathogenesis of PAH. Anoctamin-1 (Ano1), a calcium activated chloride channel, can regulate cell proliferation and cell cycle in multiple cell types. However, the expression and function of Ano1 in the pulmonary endothelium is unknown. We examined whether Ano1 was expressed in...

Introduction: Small conductance calcium (Ca)-activated K (SK) channels present in the plasmalemma of ventricular cardiomyocytes (VCMs) are dormant in health and become functional in cardiac disease. We recently showed that SK channels contribute to VCM repolarization in a rat model of hypertrophy induced by thoracic aortic banding (TAB), despite re...

http://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_494953.pdf

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses o...

Small conductance Ca2+ activated K+ (SK) channels are thought to play significant roles in ventricular arrhythmias. It has been hypothesized that increase in Ca2+ sensitivity is the main underlying cause of functional upregulation of SKs in diseased hearts. We developed the protocol to assess Ca2+ sensitivity using simultaneous recordings of curren...

Cardiac fibroblasts (CFs) are one o the most abundant cell types in the heart and play key roles in regulating myocardial physiological function and pathophysiological remodeling especially for the cardiac fibrosis. The levels of Angiotensin II (AT-II) are increased in the remodeling heart and Angiotensin signaling participates in pathological CF p...

Mitochondrial Ca(2+) homeostasis-composed of the balance of Ca(2+) influx and efflux-is responsible for the control of numerous cellular functions, including energy metabolism, the generation of reactive oxygen species, the spatiotemporal dynamics of Ca(2+) signaling, as well as cell growth and death. Recent discovery of the molecular identity of t...

Heart failure (HF) occurs in response to various types of stimulus including G q ‐protein coupled receptor (G q PCR) stimulation. G q PCR‐mediated mitochondrial dysfunction is frequently observed in HF animal models, but the molecular mechanism remains unclear. Recently, Protein kinase D (PKD) located at G q PCR downstream has been recognized as a...

Human pedigrees carrying the ryanodine receptor type 1 (RyR1) mutations frequently show skeletal muscle (SM) disorders including malignant hyperthermia (MH). There are also case reports describing sudden cardiac death (SCD) in MH patients in the conscious condition without anesthesia. These observations cannot be explained as a secondary effect of...

Cardiac fibroblasts (CFs) are the most prevalent cell type in the heart in addition to cardiomyocytes and play key roles in regulating myocardial physiological function and pathophysiological remodeling. Clinical observations and basic research data strongly suggest that CFs can respond to various stimuli including, angiotensin II (AT‐II), the leve...

Introduction Mitochondrial Ca ²⁺ uptake via the mitochondrial Ca ²⁺ uniporter (MCU) is critical for the cardiomyocyte survival and death. Basal tyrosine phosphorylation (P‐Y) of MCU was reported from mass spectroscopy of human tissues. However, it is still unclear whether the post‐translational modifications of the MCU (e.g. phosphorylation) modula...

Content of particular proteins indicating cellular injury due to apoptosis and necrosis has been investigated in ischemic/reperfused (IR) hearts and ischemic/reperfused hearts treated with CaMKII inhibitor and/or AT1 receptor inhibitor. This data article provides information in support of the original research article “Oxidative activation of CaMKI...

Chronic stimulation of PKC signaling pathways is a hallmark of cardiac disease. Although QT prolongation and arrhythmias have been associated with cardiac disease, the mechanism underlying this prolongation has not been fully understood. Using a combination of time-lapse confocal microscopy and patch-clamp techniques we investigated the time-depend...

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated at dow...

Glycogen Synthase Kinase‐3β (GSK‐3β) is proposed as one of the key molecules that regulate cell death during ischemia reperfusion (IR) injury in the heart, largely via modulating mitochondria permeability transition pore (mPTP) activity, where both Ca ²⁺ and oxidative stress are at peak levels. However, the exact mechanism of how GSK‐3β controls ca...

Regulation of mitochondrial morphology and dynamics is essential for maintaining cardiomyocyte function. Abnormal mitochondrial morphology and mitochondrial dysfunction are frequently observed in both human heart failure (HF) and animal HF models. However, it is still unclear which cardiac signaling pathway(s) regulate(s) mitochondrial morphology/f...

Mitochondrial Ca2+ has a critical role for balancing cell survival and death. Ca2+ influx into mitochondrial matrix is mediated primarily by the mitochondrial calcium uniporter (MCU). However, the signaling pathways that regulate MCU channel functions via post-translational modifications of MCU are completely unknown. Here we show that adrenergic s...

Regulation of mitochondrial morphology and dynamics is crucial for the maintenance of various cellular functions in cardiomyocytes. Abnormal mitochondrial morphologies concomitant with mitochondrial dysfunction are frequently observed both in human heart failure (HF) and in animal HF models. However, it is still unclear which cardiac signaling path...

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The most common inherited cardiac arrhythmia, LQT1, is due to IKs potassium channel mutations and is linked to high risk of adrenergic-triggered cardiac events. We recently showed that although exercise triggered events are very well treated by ß-blockers for these patients, acute arousal triggered event rate were not significantly reduced after be...

Mitochondrial Ca2+ controls numerous cell functions, such as energy metabolism, reactive oxygen species generation, spatiotemporal dynamics of Ca2+ signaling, cell growth and death in various cell types including neurons. Mitochondrial Ca2+ accumulation is mainly mediated by the mitochondrial Ca2+ uniporter (MCU), but recent reports also indicate t...

Mutations of the type 1 isoform of the ryanodine receptor (RyR1) form leaky channels and exhibit inherited skeletal muscle disorders including malignant hyperthermia (MH). Cardiac arrhythmias and sudden cardiac death in MH patients are also frequently observed during anesthesia or even under the conscious condition, but the mechanism is still unkno...

Mitochondrial Ca ²⁺ homeostasis controls the balance of cell survival and death. The molecular identity of the mitochondrial Ca ²⁺ uniporter (MCU) has been just reported and basal tyrosine phosphorylation of MCU was shown in mass spectroscopy of human tissues. However, the physiological and pathophysiological relevance of MCU post‐translational mod...

Introduction: Mitochondrial Ca ²⁺ homeostasis is crucial for balancing cell survival and death. The recent breakthrough discovery of the molecular identity of the mitochondrial Ca ²⁺ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study the role of mitochondrial Ca ²⁺ regulation in cardiac cells. Basal tyrosine phosp...

Significance: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics...

Ca(2+) influx to mitochondria is an important trigger for both mitochondrial dynamics and ATP generation in various cell types including cardiac cells. Mitochondrial Ca(2+) influx is mainly mediated by the mitochondrial Ca(2+) uniporter (MCU). Growing evidence also indicates that mitochondrial Ca(2+)-influx mechanisms are regulated not solely by MC...