Abstract 15178: Mitochondrial Dynamic Modulators Mitigates Mitochondrial Dynamic Index, Biogenesis and Metabolic Impairments in Prediabetic Rats With Cardiac Ischemia-reperfusion Injury

Introduction: Long-term exposure to high-fat diet (HFD) caused obesity, which not only was positively associated with cardiovascular disorders but also had a negative impact on the outcome of acute myocardial ischemia-reperfusion (I/R) injury. Uncontrolled fission and diminished fusion of cardiac mitochondria augment the impairment of mitochondrial biogenesis and metabolism which have been implicated in metabolic diseases and I/R injury pathology. Since cardioprotective efficacy of acute administration of mitochondrial fission inhibitor (Mdivi-1) and fusion promoter (M1) have previously been reported, the effects of chronic treatment with both modulators on cardiac mitochondrial dynamics, biogenesis and lipid metabolism in prediabetic rats subjected to cardiac I/R injury have never been elucidated. Hypothesis: Chronic treatment of Mdivi-1 and M1 after acute myocardial I/R improve mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats. Methods: Male Wistar rats (n=18) were fed with HFD. After 12 weeks, all rats were randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMd (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection for 14 days. Then, all rats underwent 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 120 minutes. The expression of mitochondrial dynamics (p-Drp1 ser616 per Mfn2 ratio or dynamic index), biogenesis (PGC1- α) and lipid metabolism (CPT1) proteins from ischemic area of heart were determined. Results: Chronic treatment of Mdivi-1 and M1 similarly improved cardiac mitochondrial dynamic index (p-Drp1 ser616 per Mfn2 ratio), increased PGC1-α and CPT1 expression levels, when compared to HFV (Fig). Conclusions: Modulating mitochondrial dynamics by chronic treatment of Mdivi-1 and M1 improved cardiac mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats following acute myocardial I/R injury.

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Abstract P049: Circadian Clock Dysfunction Impairs Mitochondrial Fitness And Contributes To Myocardial Ischemic Injury

Hypertension ◽

10.1161/hyp.76.suppl_1.p049 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Inna Rabinovich-Nikitin ◽

Illana Posen ◽

Victoria Margulets ◽

Tami A Martino ◽

Lorrie A Kirshenbaum

Keyword(s):

Quality Control ◽

Cell Viability ◽

Circadian Clock ◽

Cardiac Myocytes ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Mitochondrial Fission ◽

Control Mechanisms ◽

Complex Activity ◽

Mitochondrial Dynamic

Cardiac function is highly reliant on mitochondrial oxidative metabolism and fitness. The circadian clock is critically linked to vital physiological process including mitochondrial fission, fusion and quality control mechanisms. However, little is known of how the circadian clock regulates these vital processes in the heart. Herein, we identified a putative circadian Clock - mitochondrial interactome that gates an adaptive stress response for cell viability during myocardial ischemia reperfusion (I-R) injury. We show that Clock transcriptionally coordinates expression of mitochondrial dynamic fusion and fission, bioenergetic and quality control proteins in cardiac myocytes. Transcriptome and gene ontology mapping revealed Clock defective hearts subjected to I-R exhibited major transcriptional deficits in several key survival processes including mitochondrial dynamics, bioenergetics and autophagy that were reduced further following I-R. Gain of function of Clock activity re-established gene transcription of mitochondrial respiratory complex activity, quality control mechanisms and cell viability. Collectively, our data show that mitochondrial fitness and cell survival is mutually dependent upon and obligatorily linked to transcription of the circadian Clock gene in cardiac myocytes. Our data suggest the functional loss of Clock activity predisposes cardiac myocytes to metabolic catastrophe. Hence, therapeutic strategies designed to preserve circadian clock activity in the hearts may prove beneficial in reducing morbidity and mortality following ischemia -related pathologies such as myocardial infarction.

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Novel Insights into the Molecular Features and Regulatory Mechanisms of Mitochondrial Dynamic Disorder in the Pathogenesis of Cardiovascular Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6669075 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Ying Tan ◽

Fengfan Xia ◽

Lulan Li ◽

Xiaojie Peng ◽

Wenqian Liu ◽

...

Keyword(s):

Cardiovascular Disease ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Mitochondrial Fission ◽

Regulatory Mechanisms ◽

Septic Cardiomyopathy ◽

Mitochondrial Dynamic ◽

Dynamic Disorder ◽

Molecular Features ◽

And Function

Mitochondria maintain mitochondrial homeostasis through continuous fusion and fission, that is, mitochondrial dynamics, which is precisely mediated by mitochondrial fission and fusion proteins, including dynamin-related protein 1 (Drp1), mitofusin 1 and 2 (Mfn1/2), and optic atrophy 1 (OPA1). When the mitochondrial fission and fusion of cardiomyocytes are out of balance, they will cause their own morphology and function disorders, which damage the structure and function of the heart, are involved in the occurrence and progression of cardiovascular disease such as ischemia-reperfusion injury (IRI), septic cardiomyopathy, and diabetic cardiomyopathy. In this paper, we focus on the latest findings regarding the molecular features and regulatory mechanisms of mitochondrial dynamic disorder in cardiovascular pathologies. Finally, we will address how these findings can be applied to improve the treatment of cardiovascular disease.

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Sphingolipids and Mitochondrial Dynamic

Cells ◽

10.3390/cells9030581 ◽

2020 ◽

Vol 9 (3) ◽

pp. 581 ◽

Cited By ~ 6

Author(s):

Lais Brigliadori Fugio ◽

Fernanda B. Coeli-Lacchini ◽

Andréia Machado Leopoldino

Keyword(s):

Cell Fate ◽

Metabolic Diseases ◽

Mitochondrial Dynamics ◽

Mitochondrial Dynamic ◽

Sphingosine 1 Phosphate ◽

Mitochondria Dynamics ◽

Human Disorders ◽

Cell Type Specific ◽

Immune System Regulation ◽

Ceramide Synthases

For decades, sphingolipids have been related to several biological functions such as immune system regulation, cell survival, and proliferation. Recently, it has been reported that sphingolipids could be biomarkers in cancer and in other human disorders such as metabolic diseases. This is evidenced by the biological complexity of the sphingolipids associated with cell type-specific signaling and diverse sphingolipids molecules. As mitochondria dynamics have serious implications in homeostasis, in the present review, we focused on the relationship between sphingolipids, mainly ceramides and sphingosine-1-phosphate, and mitochondrial dynamics directed by fission, fusion, and mitophagy. There is evidence that the balances of ceramides (C18 and C16) and S1P, as well as the location of specific ceramide synthases in mitochondria, have roles in mitophagy and fission with an impact on cell fate and metabolism. However, signaling pathways controlling the sphingolipids metabolism and their location in mitochondria need to be better understood in order to propose new interventions and therapeutic strategies.

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Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms21186919 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6919

Author(s):

Monika Okuliarova ◽

Valentina Sophia Rumanova ◽

Katarina Stebelova ◽

Michal Zeman

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Metabolic Diseases ◽

De Novo ◽

Negative Impact ◽

Acid Uptake ◽

Control Mechanisms ◽

Light At Night ◽

Dim Light

Dim light at night (dLAN) is associated with metabolic risk but the specific effects on lipid metabolism have only been evaluated to a limited extent. Therefore, to explore whether dLAN can compromise lipid metabolic homeostasis in healthy individuals, we exposed Wistar rats to dLAN (~2 lx) for 2 and 5 weeks and analyzed the main lipogenic pathways in the liver and epididymal fat pad, including the control mechanisms at the hormonal and molecular level. We found that dLAN promoted hepatic triacylglycerol accumulation, upregulated hepatic genes involved in de novo synthesis of fatty acids, and elevated glucose and fatty acid uptake. These observations were paralleled with suppressed fatty acid synthesis in the adipose tissue and altered plasma adipokine levels, indicating disturbed adipocyte metabolic function with a potential negative impact on liver metabolism. Moreover, dLAN-exposed rats displayed an elevated expression of two peroxisome proliferator-activated receptor family members (Pparα and Pparγ) in the liver and adipose tissue, suggesting the deregulation of important metabolic transcription factors. Together, our results demonstrate that an impaired balance of lipid biosynthetic pathways caused by dLAN can increase lipid storage in the liver, thereby accounting for a potential linking mechanism between dLAN and metabolic diseases.

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Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

Cell Death and Disease ◽

10.1038/s41419-021-03752-2 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Anthony R. Anzell ◽

Garrett M. Fogo ◽

Zoya Gurm ◽

Sarita Raghunayakula ◽

Joseph M. Wider ◽

...

Keyword(s):

Cortical Neurons ◽

Ischemia Reperfusion Injury ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Mitochondrial Fission ◽

Conditional Knockout ◽

Mitochondrial Morphology ◽

Primary Neurons ◽

Mitochondrial Fragmentation

AbstractMitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.

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The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases

Journal of Diabetes Research ◽

10.1155/2018/9363461 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Lei Zhang ◽

Qun Wang ◽

Wen Liu ◽

Fangyan Liu ◽

Ailing Ji ◽

...

Keyword(s):

Skeletal Muscle ◽

Lipid Metabolism ◽

Nuclear Receptor ◽

Metabolic Diseases ◽

Early Response ◽

Orphan Receptor ◽

Special Focus ◽

Orphan Nuclear Receptor ◽

Physiological Functions ◽

The Impact

Orphan nuclear receptor 4A1 (NR4A1) is a transcriptional factor of the nuclear orphan receptor (NR4A) superfamily that has sparked interest across different research fields in recent years. Several studies have demonstrated that ligand-independent NR4A1 is an immediate-early response gene and the protein product is rapidly induced by a variety of stimuli. Hyperfunction or dysfunction of NR4A1 is implicated in various metabolic processes, including carbohydrate metabolism, lipid metabolism, and energy balance, in major metabolic tissues, such as liver, skeletal muscle, pancreatic tissues, and adipose tissues. No endogenous ligands for NR4A1 have been identified, but numerous compounds that bind and activate or inactivate nuclear NR4A1 or induce cytoplasmic localization of NR4A1 have been identified. This review summarizes recent advances in our understanding of the molecular biology and physiological functions of NR4A1. And we focus on the physiological functions of NR4A1 receptor to the development of the metabolic diseases, with a special focus on the impact on carbohydrate and lipid metabolism in skeletal muscle, liver, adipose tissue, and islet.

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Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia–Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-021-07250-7 ◽

2021 ◽

Author(s):

Chayodom Maneechote ◽

Sasiwan Kerdphoo ◽

Thidarat Jaiwongkam ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Myocardial Ischemia ◽

Mitochondrial Dysfunction ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Pharmacological Modulation ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

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Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury

Circulation ◽

10.1161/circ.142.suppl_3.14412 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jing Yang ◽

Geoffrey W CHO ◽

Lihao He ◽

Yuxin Chu ◽

Jin He ◽

...

Keyword(s):

Infarct Size ◽

Reperfusion Injury ◽

Mitochondrial Dynamics ◽

Systolic Function ◽

Ischemia Reperfusion ◽

Border Zone ◽

Autophagic Flux ◽

Hdac Inhibition ◽

Infarct Border Zone ◽

Infarct Border

Background and Hypothesis: Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.

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