Sang‐Bing Ong

Hong Kong Adventist Hospital

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Derek J. Hausenloy

University College London

Nur Izzah Ismail

Chinese University of Hong Kong

Sang‐Ging Ong

University of Illinois Chicago

Derek M. Yellon

University College London

Dachun Xu

Shanghai Tenth People's Hospital

Héctor A. Cabrera-Fuentes

Imam Abdulrahman Bin Faisal University

Won Hee Lee

University of Arizona

Andrew Hall

AstraZeneca (United Kingdom)

Khairunnisa Katwadi

Duke-NUS Medical School

Sean M. Davidson

University College London

Cooperative Institutions

Inserm

152

Centre National de la Recherche Scientifique

134

University of Michigan–Ann Arbor

126

Harvard University

125

University College London

106

Chinese Academy of Sciences

National Institutes of Health

Istituti di Ricovero e Cura a Carattere Scientifico

Instituto de Salud Carlos III

Johns Hopkins University

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Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-1

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2020)

Wataru Ohwada Masaya Tanno Toshiyuki Yano Sang‐Bing Ong Koki Abe

ERK and Akt have been shown to regulate cell sensitivity to death-inducing stress by phosphorylating GSK-3β, a major modulator of the threshold for mitochondrial permeability transition. Here we examined intra-mitochondrial localization of the pro-survival kinases and their regulation by phosphatases. Stepwise trypsin digestion of mitochondria isolated from HEK293 or H9c2 cells was performed, and immunoblotting revealed that GSK-3β and ERK localized dominantly in the outer membrane (OM), while Akt resided at comparable levels in OM, the inner membrane (IM) and the matrix. Treatment with IGF-1 increased the protein level of Akt in the matrix, while ERK and GSK-3β protein levels were increased in OM. Simultaneously, IGF-1 treatment elevated the level of Thr202/Tyr204-phospho-ERK in IM and matrix and levels of Ser473-phospho-Akt and Ser9-phospho-GSK-3β in OM, IM and matrix. Exposing cells to reactive oxygen species (ROS) by using antimycin A increased the levels of DUSP5 and PHLPP-1 mainly in OM and induced dephosphorylation of Akt, ERK and GSK-3β. The mitochondrial localization of DUSP5 was confirmed by experiments with mitochondria purified by Percoll gradient centrifugation and by transfection of cells with GFP-tagged DUSP5. Knockdown of either DUSP5 or PHLPP-1 increased the levels of both Thr202/Tyr204-phospho-ERK and Ser473-phospho-Akt in mitochondria. Cell death induced by antimycin A was suppressed by siRNA-mediated knockdown of DUSP5. The results suggest that Akt and ERK in mitochondria show distinct intra-mitochondrial localization and crosstalk in GSK-3β regulation and that recruitment of DUSP5 as well as PHLPP-1 to mitochondria contributes to ROS-induced termination of the protective signaling.

10.1016/j.bbadis.2020.165851

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Citations (4)

The Calcineurin-Drp1-Mediated Mitochondrial Fragmentation Is Aligned with the Differentiation of c-Kit Cardiac Progenitor Cells

International Journal of Stem Cells (2022)

Attaur Rahman Yuhao Li Nur Izzah Ismail To-Kiu Chan Yuzhen Li

The heart contains a pool of c-kit+ progenitor cells which is believed to be able to regenerate. The differentiation of these progenitor cells is reliant on different physiological cues. Unraveling the underlying signals to direct differentiation of progenitor cells will be beneficial in controlling progenitor cell fate. In this regard, the role of the mitochondria in mediating cardiac progenitor cell fate remains unclear. Specifically, the association between changes in mitochondrial morphology with the differentiation status of c-kit+ CPCs remains elusive. In this study, we investigated the relationship between mitochondrial morphology and the differentiation status of c-kit+ progenitor cells.c-kit+ CPCs were isolated from 2-month-old male wild-type FVB mice. To activate differentiation, CPCs were incubated in α-minimal essential medium containing 10 nM dexamethasone for up to 7 days. To inhibit Drp1-mediated mitochondrial fragmentation, either 10 μM or 50 μM mdivi-1 was administered once at Day 0 and again at Day 2 of differentiation. To inhibit calcineurin, either 1 μM or 5 μM ciclosporin-A (CsA) was administered once at Day 0 and again at Day 2 of differentiation. Dexamethasone-induced differentiation of c-kit+ progenitor cells is aligned with fragmentation of the mitochondria via a calcineurin-Drp1 pathway. Pharmacologically inhibiting mitochondrial fragmentation retains the undifferentiated state of the c-kit+ progenitor cells.The findings from this study provide an alternative view of the role of mitochondrial fusion-fission in the differentiation of cardiac progenitor cells and the potential of pharmacologically manipulating the mitochondria to direct progenitor cell fate.

Progenitor

Cell fate determination

Fragmentation

10.15283/ijsc22141

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Citations (2)

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury

PLoS ONE (2013)

Hilary K. Siddall Derek M. Yellon Sang‐Bing Ong Uma Mukherjee Niall Burke

Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction.Over-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2±5.2% PINK1 versus 49.0±2.4% control; N = 320 cells/group P<0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P<0.05). Hearts excised from PINK1+/+, PINK1+/- and PINK1-/- mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1-/- hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/- hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/- versus 51.5±4.3% PINK1-/- hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1-/- hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1.We show that the loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection.

PINK1

MPTP

10.1371/journal.pone.0062400

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Citations (122)

Characterization of a Novel Mitophagy-Related 5-Genes Signature for Diagnosis of Acute Myocardial Infarction

Yanhua Xu Yang Su Teng Ma Yaqi Zhang Xin Pan

Signature (topology)

Characterization

10.2139/ssrn.4741169

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Long COVID-19 and the Heart: Is Cardiac Mitochondria the Missing Link?

Antioxidants and Redox Signaling (2022)

Xing Chang Nur Izzah Ismail Attaur Rahman Dachun Xu Renee W. Y. Chan

Although corona virus disease 2019 (COVID-19) has now gradually been categorized as an endemic, the long-term effect of COVID-19 in causing multiorgan disorders, including a perturbed cardiovascular system, is beginning to gain attention. Nonetheless, the underlying mechanism triggering post-COVID-19 cardiovascular dysfunction remains enigmatic. Are cardiac mitochondria the key to mediating cardiac dysfunction post-severe acute respiratory syndrome coronavirus 2 (post-SARS-CoV-2) infection?

Viral Myocarditis

Cardiac Dysfunction

10.1089/ars.2022.0126

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Citations (30)

A new parameter to simultaneously assess antioxidant activity for multiple phenolic compounds present in food products

Food Chemistry (2017)

Hong Yang Xuejia Xue Huan Li Su Chin Tay-Chan Sang‐Bing Ong

Food Products

Limiting

ABTS

10.1016/j.foodchem.2017.02.022

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Citations (3)

“Pack year” smoking histories: what about patients who use loose tobacco?: Table 1

Tobacco Control (2005)

David M. Wood M G Mould Sang‐Bing Ong Emma H. Baker

Life time smoking of ready made cigarettes can be readily quantified as "pack years" smoked, but methods for measuring loose tobacco use are less well established. In this study the frequency of loose tobacco use by 247 hospital in-patients was determined; 64% were current or ex-smokers, 41.3% of whom (25.9% of participants) had smoked loose tobacco. A formula was developed for converting loose tobacco use to pack years smoked, based on the weight of tobacco in ready made cigarettes; 12.5 g or half an ounce of loose tobacco was approximately equivalent to one packet of 20 cigarettes. Using a questionnaire it was found that hospital physicians of all grades were able to convert smoking histories of ready made cigarettes, but not loose tobacco, into number of "pack years" smoked.

Fluid ounce (US)

Smoking history

Smoking epidemiology

10.1136/tc.2004.009977

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DJ-1 protects against cell death following acute cardiac ischemia–reperfusion injury

Cell Death and Disease (2014)

R K Dongworth U A Mukherjee A R Hall Rónan Astin Sang‐Bing Ong

Abstract Novel therapeutic targets are required to protect the heart against cell death from acute ischemia–reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson’s disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia–reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n =5, P <0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n =6, P <0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n =6 cells, P <0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1 L166P and DJ-1 Cys106A mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n ≥7, P <0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.

MPTP

10.1038/cddis.2014.41

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Citations (72)

Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor

Cardiovascular Research (2023)

Sarath Babu Nukala Jordan Jousma Gege Yan Zhenbo Han Youjeong Kwon

Abstract Aims Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi-receptor tyrosine kinase inhibitor, has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and results We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human-induced pluripotent stem cell-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to down-regulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirmed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and up-regulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in Has2os and degradation of the endothelial glycocalyx. Finally, we identified that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.

Glycocalyx

10.1093/cvr/cvad087

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Citations (5)

High Performance Liquid Chromatography Fingerprinting Technology Of The Commonly-Used Traditional Chinese Medicine Herbs

Baochang Cai Sang‐Bing Ong Xunhong Liu

Chinese herbs

10.1142/9789814291101

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Citations (5)