HS-1793 protects C2C12 cells from oxidative stress via mitochondrial function regulation

MARQUEZ JUBERT,Park Nammi,Maria Victoria Faith Garcia,Kim Hyoung Kyu,Han Jin 대한독성 유전단백체 학회 2020 Molecular & cellular toxicology Vol.16 No.4

Background HS1793, a novel analogue of resveratrol, was previously determined to be more potent at lower dosages by improving mitochondrial function and increased mitochondrial biogenesis-related proteins. In this study, we focused on targeting the mitochondria to address muscle wasting with HS-1793. Method Dosage screening was performed by evaluating for cytotoxicity and cell proliferation. Mitochondrial mass, mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) level, and mitochondria biogenesis-regulated genes and proteins were analyzed to determine the efects on mitochondrial biogenesis. Results HS-1793 reduced ROS generation, but treatment did not interfere with cellular viability at low dosages. HS-1793 also regulated mitochondrial function by increasing cellular and mitochondrial ATP synthesis function, stabilizing Δψm and decreasing ROS. More importantly, these dysfunction in these parameters were ameliorated by HS-1793 in a simulated oxidative stress model with tBHP. We also observed increase in mitochondrial mass and upregulation in vital mitochondrial biogenesis-related gene PGC1-α as a response to HS-1793 treatment. Moreover, phosphorylation of AKT and mTOR proteins, which are considered as regulators of skeletal muscle function were also increased during the treatment. Finally, HS-1793 also demonstrated protective efects against cisplatin-induced skeletal muscle cell injury by increasing expression of mitochondrial biogenesis-relate markers. Conclusion Taken altogether, it shows the viability of HS-1793 as a compound that can restore mitochondrial function and render protection in skeletal muscle cells, especially during high oxidative stress levels.

You're Not under Arrest: Worry-free with β-arrestin

Jubert Marquez,한진 대한심장학회 2018 Korean Circulation Journal Vol.48 No.4

Definitely not lost in translation: post-translational modifications of cardiac mitochondrial proteins in cardiovascular disease

Jubert Marquez,이성률,김나리,한진 대한심장학회 2016 Korean Circulation Journal Vol.46 No.1

Protein post-translational modifications (PTMs) are crucial in regulating cellular biology by playing key roles in processes such as the rapid on and off switching of signaling network and the regulation of enzymatic activities without affecting gene expressions. PTMs lead to conformational changes in the tertiary structure of protein and resultant regulation of protein function such as activation, inhibition, or signaling roles. PTMs such as phosphorylation, acetylation, and S-nitrosylation of specific sites in proteins have key roles in regulation of mitochondrial functions, thereby contributing to the progression to heart failure. Despite the extensive study of PTMs in mitochondrial proteins much remains unclear. Further research is yet to be undertaken to elucidate how changes in the proteins may lead to cardiovascular and metabolic disease progression in particular. We aimed to summarize the various types of PTMs that occur in mitochondrial proteins, which might be associated with heart failure. This study will increase the understanding of cardiovascular diseases through PTM

Rescue of Heart Failure by Mitochondrial Recovery

Jubert Marquez,이성률,김나리,한진 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.1

Heart failure (HF) is a multifactorial disease brought about by numerous, and oftentimes complex, etiological mechanisms. Although well studied, HF continues to affect millions of people worldwide and current treatments can only prevent further progression of HF. Mitochondria undoubtedly play an important role in the progression of HF, and numerous studies have highlighted mitochondrial components that contribute to HF. This review presents an overview of the role of mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial permeability transition pore in HF, discusses ongoing studies that attempt to address the disease through mitochondrial targeting, and provides an insight on how these studies can affect future research on HF treatment.

Phosphorylation in Novel Mitochondrial Creatine Kinase Tyrosine Residues Render Cardioprotection against Hypoxia/Reoxygenation Injury

박남미,MARQUEZ JUBERT,Garcia Maria Victoria Faith,Shimizu Ippei,이성률,김형규,한진 한국지질동맥경화학회 2021 지질·동맥경화학회지 Vol.10 No.2

Objective: Ischemic cardiomyopathy (ICM) is the leading cause of heart failure. Proteomic and genomic studies have demonstrated ischemic preconditioning (IPC) can assert cardioprotection against ICM through mitochondrial function regulation. Considering IPC is conducted in a relatively brief period, regulation of protein expression also occurs very rapidly, highlighting the importance of protein function modulation by post-translational modifications. This study aimed to identify and analyze novel phosphorylated mitochondrial proteins that can be harnessed for therapeutic strategies for preventing ischemia/reperfusion (I/R) injury. Methods: Sprague-Dawley rat hearts were used in an ex vivo Langendorff system to simulate normal perfusion, I/R, and IPC condition, after which the samples were prepared for phosphoproteomic analysis. Employing human cardiomyocyte AC16 cells, we investigated the cardioprotective role of CKMT2 through overexpression and how site-directed mutagenesis of putative CKMT2 phosphorylation sites (Y159A, Y255A, and Y368A) can affect cardioprotection by measuring CKMT2 protein activity, mitochondrial function and protein expression changes. Results: The phosphoproteomic analysis revealed dephosphorylation of mitochondrial creatine kinase (CKMT2) during ischemia and I/R, while preserving its phosphorylated state during IPC. CKMT2 overexpression conferred cardioprotection against hypoxia/reoxygenation (H/R) by increasing cell viability and mitochondrial adenosine triphosphate level, preserving mitochondrial membrane potential, and reduced reactive oxygen species (ROS) generation, while phosphomutations, especially in Y368, nullified cardioprotection by significantly reducing cell viability and increasing ROS production during H/R. CKMT2 overexpression increased mitochondrial function by mediating the proliferator-activated receptor γ coactivator-1α/estrogen-related receptor-α pathway, and these effects were mostly inhibited by Y368A mutation. Conclusion: These results suggest that regulation of quantitative expression and phosphorylation site Y368 of CKMT2 offers a unique mechanism in future ICM therapeutics.

The role of decorin in cardiovascular diseases: more than just a decoration

Vu, Thu Thi,Marquez, Jubert,Le, Long Thanh,Nguyen, Anh Thi Tuyet,Kim, Hyoung Kyu,Han, Jin Harwood Academic 2018 Free radical research Vol.52 No.11

Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts

Ko, Tae Hee,Marquez, Jubert C.,Kim, Hyoung Kyu,Jeong, Seung Hun,Lee, SungRyul,Youm, Jae Boum,Song, In Sung,Seo, Dae Yun,Kim, Hye Jin,Won, Du Nam,Cho, Kyoung Im,Choi, Mun Gi,Rhee, Byoung Doo,Ko, Kyung Springer-Verlag 2018 Pfl ugers Arch Vol.470 No.2

<P>Metabolic disturbance and mitochondrial dysfunction are a hallmark of diabetic cardiomyopathy (DC). Resistance exercise (RE) not only enhances the condition of healthy individuals but could also improve the status of those with disease. However, the beneficial effects of RE in the prevention of DC and mitochondrial dysfunction are uncertain. Therefore, this study investigated whether RE attenuates DC by improving mitochondrial function using an in vivo rat model of diabetes. Fourteen Otsuka Long-Evans Tokushima Fatty rats were assigned to sedentary control (SC, n = 7) and RE (n = 7) groups at 28 weeks of age. Long-Evans Tokushima Otsuka rats were used as the non-diabetic control. The RE rats were trained by 20 repetitions of climbing a ladder 5 days per week. RE rats exhibited higher glucose uptake and lower lipid profiles, indicating changes in energy metabolism. RE rats significantly increased the ejection fraction and fractional shortening compared with the SC rats. Isolated mitochondria in RE rats showed increase in mitochondrial numbers, which were accompanied by higher expression of mitochondrial biogenesis proteins such as proliferator-activated receptor-gamma coactivator-1 alpha and TFAM. Moreover, RE rats reduced proton leakage and reactive oxygen species production, with higher membrane potential. These results were accompanied by higher superoxide dismutase 2 and lower uncoupling protein 2 (UCP2) and UCP3 levels in RE rats. These data suggest that RE is effective at ameliorating DC by improving mitochondrial function, which may contribute to the maintenance of diabetic cardiac contractility.</P>

Mitochondrial calcium uniporter inhibition attenuates mouse bone marrow-derived mast cell degranulation induced by beta-1,3-glucan

Dang, Van Cuong,Kim, Hyoung Kyu,Marquez, Jubert,Kim, Nari,Ko, Kyung Soo,Rhee, Byoung Doo,Han, Jin The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.2

Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular $Ca^{2+}$, which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with $0.5{\mu}g/ml$ BG, $100{\mu}g/ml$ peptidoglycan (PGN), or $10{\mu}M$ A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium-free conditions. Ruthenium red, a mitochondrial $Ca^{2+}$ uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial $Ca^{2+}$ uniporter has an important regulatory role in BG-induced mast cell degranulation.

Cyclic stretch increases mitochondrial biogenesis in a cardiac cell line

Kim, Hyoung Kyu,Kang, Yun Gyeong,Jeong, Seung Hun,Park, Nammi,Marquez, Jubert,Ko, Kyung Soo,Rhee, Byoung Doo,Shin, Jung-Woog,Han, Jin Elsevier 2018 Biochemical and biophysical research communication Vol.505 No.3

<P><B>Abstract</B></P> <P>Unlike stable and immobile cell line conditions, animal hearts contract and relax to pump blood throughout the body. Mitochondria play an essential role by producing biological energy molecules to maintain heart function. In this study, we assessed the effect of heart mimetic cyclic stretch on mitochondria in a cardiac cell line. To mimic the geometric and biomechanical conditions surrounding cells in vivo, cyclic stretching was performed on HL-1 murine cardiomyocytes seeded onto an elastic micropatterned substrate (10% elongation, 0.5 Hz, 4 h/day). Cell viability, semi-quantitative Q-PCR, and western blot analyses were performed in non-stimulated control and cyclic stretch stimulated HL-1 cell lines. Cyclic stretch significantly increased the expression of mitochondria biogenesis-related genes (TUFM, TFAM, ERRα, and PGC1-α) and mitochondria oxidative phosphorylation-related genes (PHB1 and CYTB). Western blot analysis confirmed that cyclic stretch increased protein levels of mitochondria biogenesis-related proteins (TFAM, and ERRα) and oxidative phosphorylation-related proteins (NDUFS1, UQCRC, and PHB1). Consequently, cyclic stretch increased mitochondrial mass and ATP production in treated cells. Our results suggest that cyclic stretch transcriptionally enhanced mitochondria biogenesis and oxidative phosphorylation without detrimental effects in a cultured cardiac cell line.</P>

NecroX-5 protects mitochondrial oxidative phosphorylation capacity and preserves PGC1α expression levels during hypoxia/reoxygenation injury

Vu, Thi Thu,Kim, Hyoung Kyu,Le, Thanh Long,Nyamaa, Bayalagmaa,Song, In-Sung,To, Thanh Thuy,Nguyen, Quang Huy,Marquez, Jubert,Kim, Soon Ha,Kim, Nari,Ko, Kyung Soo,Rhee, Byoung Doo,Han, Jin The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.2

Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment ($10{\mu}M$) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-$1{\alpha}$ ($PGC1{\alpha}$) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving $PGC1{\alpha}$ during cardiac HR injuries.