Mitochondrial Injury and Targeted Intervention in Septic Cardiomyopathy

2019 ◽  
Vol 25 (18) ◽  
pp. 2060-2070 ◽  
Author(s):  
Ying Tan ◽  
Sainan Chen ◽  
Jiankai Zhong ◽  
Jun Ren ◽  
Maolong Dong
Keyword(s):  
Clinical Work ◽  
Multiple Organ ◽  
Mitochondrial Morphology ◽  
Septic Cardiomyopathy ◽  
Mitochondrial Injury ◽  
Main Culprit ◽  
Cardiac Contractile Dysfunction ◽  
Underlying Mechanisms ◽  
Sepsis And Septic Shock ◽  
And Function

Background: Sepsis and septic shock are known to prompt multiple organ failure including cardiac contractile dysfunction, which is typically referred to as septic cardiomyopathy. Among various theories postulated for the etiology of septic cardiomyopathy, mitochondrial injury (both morphology and function) in the heart is perceived as the main culprit for reduced myocardial performance and ultimately heart failure in the face of sepsis. Methods: Over the past decades, ample of experimental and clinical work have appeared, focusing on myocardial mitochondrial changes and related interventions in septic cardiomyopathy. Results and Conclusion: Here we will briefly summarize the recent experimental and clinical progress on myocardial mitochondrial morphology and function in sepsis, and discuss possible underlying mechanisms, as well as the contemporary interventional options.

scholarly journals Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

2018 ◽  
Vol 46 (4) ◽  
pp. 1668-1682 ◽  
Author(s):  
Yu Zhou ◽  
Siheng Lian ◽  
Jin Zhang ◽  
Donghai Lin ◽  
Caihua Huang ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Metabolic Pathways ◽  
Mitochondrial Dynamics ◽  
Diabetic Rats ◽  
Morris Water Maze Test ◽  
Mitochondrial Morphology ◽  
Underlying Mechanisms ◽  
And Function ◽  
Energy Failure

Background/Aims: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. Methods: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. Results: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. Conclusion: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future.

Abstract 78: TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3 and NF-kB Dependent Activation of OPA1 Expression

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jing-Liang Nan ◽  
Wei Zhu ◽  
Ying-Chao Wang ◽  
Zhi-Wei Zhong ◽  
Lian-lian Zhu ◽  
...  
Keyword(s):  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Protective Effects ◽  
Promoter Regions ◽  
Neonatal Cardiomyocytes ◽  
Protein Levels ◽  
Dynamic Simulation Model ◽  
Underlying Mechanisms ◽  
Reported Data ◽  
And Function

Background: TNFR2 stimulation is known to possess protective effects for the cardiomyocytes, however, the underlying mechanisms remain unknown. Methods and Results: Using cultured neonatal cardiomyocytes that were infected with lentivirus containing shRNA targeting TNFR1, we showed that TNFR2 activation by TNFα (5nmol/L) resulted in increased mitochondrial fusion, mitochondrial membrane potential which were associated with both elevated intracellular ATP levels and oxygen consumption rate. Intriguingly, these changes were associated with increased protein levels of OPA1, with no changes in the expression levels of Drp1, Mfn1, Mfn2. We went further and reproduced previously reported data that NF-kB acetylation (Lys310) was increased with TNFR2 activation. Interestingly, however, we also observed dose-dependent effects on increase in Stat3 acetylation. Using shRNA approach, we then demonstrated that either Stat3 or NF-kB knockdown can attenuate TNFR2 induced OPA1 expression. The close interaction between these two signalings was validated by co-IP assay and confocal immunofluorescence staining. Aided by bio-informatics searching, we then performed ChIP assay to show that the binding sites of OPA1 promoter regions for STAT3 (-156 to -167) and NFkB (-192 to -203) were adjacent. We further validated that p300 induced Stat3 acetylation was indispensable for complex formation by the interaction between Stat3-DBD and NF-kB -ΔRHD, which in turn was a key event for OPA1 transcription activation. And silence of p300 can abolish OPA1 upregulation upon TNFR2 activation. Computerized data analysis based on zdock and zrank score followed by molecular dynamic simulation model for the whole Stat3 structure revealed higher value of the exterior dielectric constant (obtained from MM/PBSA calculation) for the two sites, K370 and K383, of Stat3, suggesting the essential roles for these two sites for Stat3-NFkB interaction, which were confirmed by co-IP with Stat3-DBD mutants (K370Q,K370R,K383Q,K383R) approach. Conclusions: Our data suggested that p300 mediated Stat3 acetylation cooperates with NF-kB to modulate TNFR2 activation induced OPA1 upregulation, leading to improved mitochondrial morphology and function.

scholarly journals Bezafibrate Improves Mitochondrial Fission and Function in DNM1L Deficient Patient Cells

2019 ◽  
Author(s):  
Liza Douiev ◽  
Ruth Sheffer ◽  
Gabriella Horvath ◽  
Ann Saada
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Mitochondrial Fission ◽  
Multiple Organ ◽  
Mitochondrial Morphology ◽  
Main Role ◽  
Atp Production ◽  
Organ Systems ◽  
Mitochondrial Functions ◽  
And Function

Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1 or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene results in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, Bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, ATP production, oxygen consumption and s improved mitochondrial morphology in patient’s fibroblasts, albeit concomitantly causing a mild increase ROS production. Further studies would be needed to show the consistency of the response to Bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that Bezafibrate could be a possible treatment option for patients with certain DNM1L mutations.

scholarly journals The Endothelial Glycocalyx: New Diagnostic and Therapeutic Approaches in Sepsis

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Lukas Martin ◽  
Patrick Koczera ◽  
Elisabeth Zechendorf ◽  
Tobias Schuerholz
Keyword(s):  
Circulatory System ◽  
Endothelial Permeability ◽  
Kidney Injury ◽  
Multiple Organ ◽  
Endothelial Glycocalyx ◽  
Septic Cardiomyopathy ◽  
Clinical Effects ◽  
Organ Failures ◽  
Life Threatening ◽  
Sepsis And Septic Shock

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The endothelial glycocalyx is one of the earliest sites involved during sepsis. This fragile layer is a complex network of cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins lining the luminal side of endothelial cells with a thickness of about 1 to 3 μm. Sepsis-associated alterations of its structure affect endothelial permeability and result in the liberation of endogenous damage-associated molecular patterns (DAMPs). Once liberated in the circulatory system, DAMPs trigger the devastating consequences of the proinflammatory cascades in sepsis and septic shock. In this way, the injury to the glycocalyx with the consecutive release of DAMPs contributes to a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and septic cardiomyopathy. Moreover, the extent of glycocalyx degradation serves as a marker of endothelial dysfunction and sepsis severity. In this review, we highlight the crucial role of the glycocalyx in sepsis as a diagnostic tool and discuss the potential of members of the endothelial glycocalyx serving as hopeful therapeutic targets in sepsis-associated multiple organ failures.

The Role of Histones and Heparin in Sepsis: A Review

2021 ◽  
pp. 088506662199232
Author(s):  
Xiaojuan Zhang ◽  
Xin Li
Keyword(s):  
Septic Shock ◽  
Multiple Organ ◽  
Clinical Settings ◽  
The Past ◽  
Life Saving ◽  
Extracellular Histones ◽  
Sepsis And Septic Shock ◽  
Development And Management ◽  
Made In

Septic shock with multiple organ failure is a devastating situation in clinical settings. Through the past decades, much progress has been made in the management of sepsis and its underlying pathogenesis, but a highly effective therapeutic has not been developed. Recently, macromolecules such as histones have been targeted in the treatment of sepsis. Histones primarily function as chromosomal organizers to pack DNA and regulate its transcription through epigenetic mechanisms. However, a growing body of research has shown that histone family members can also exert cellular toxicity once they relocate from the nucleus into the extracellular space. Heparin, a commonly used anti-coagulant, has been shown to possess life-saving capabilities for septic patients, but the potential interplay between heparin and extracellular histones has not been investigated. In this review, we summarize the pathogenic roles of extracellular histones and the therapeutic roles of heparin in the development and management of sepsis and septic shock.

scholarly journals Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 359
Author(s):  
Hsiang-Hao Chuang ◽  
Yen-Yi Zhen ◽  
Yu-Chen Tsai ◽  
Cheng-Hao Chuang ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressors ◽  
Protein Conformation ◽  
Genome Stability ◽  
Recent Progress ◽  
Multiple Roles ◽  
Cancer Development ◽  
Cancer Hallmarks ◽  
Underlying Mechanisms ◽  
And Function

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

scholarly journals Heterochronic Parabiosis: Old Blood Induces Changes in Mitochondrial Structure and Function of Young Mice

2020 ◽  
Author(s):  
Jenny L Gonzalez-Armenta ◽  
Ning Li ◽  
Rae-Ling Lee ◽  
Baisong Lu ◽  
Anthony J A Molina
Keyword(s):  
Mitochondrial Respiration ◽  
Complex I ◽  
Structure And Function ◽  
Muscle Performance ◽  
Mitochondrial Morphology ◽  
Positive Effects ◽  
Mitochondrial Structure ◽  
And Function ◽  
Old Mice ◽  
Young Mice

Abstract Heterochronic parabiosis models have been utilized to demonstrate the role of blood-borne circulating factors in systemic effects of aging. In previous studies, heterochronic parabiosis has shown positive effects across multiple tissues in old mice. More recently, a study demonstrated old blood had a more profound negative effect on muscle performance and neurogenesis of young mice. In this study, we used heterochronic parabiosis to test the hypothesis that circulating factors mediate mitochondrial bioenergetic decline, a well-established biological hallmark of aging. We examined mitochondrial morphology, expression of mitochondrial complexes, and mitochondrial respiration from skeletal muscle of mice connected as heterochronic pairs, as well as young and old isochronic controls. Our results indicate that young heterochronic mice had significantly lower total mitochondrial content and on average had significantly smaller mitochondria compared to young isochronic controls. Expression of complex IV followed a similar pattern: young heterochronic mice had a trend for lower expression compared to young isochronic controls. Additionally, respirometric analyses indicate that young heterochronic mice had significantly lower complex I, complex I + II, and maximal mitochondrial respiration and a trend for lower complex II-driven respiration compared to young isochronic controls. Interestingly, we did not observe significant improvements in old heterochronic mice compared to old isochronic controls, demonstrating the profound deleterious effects of circulating factors from old mice on mitochondrial structure and function. We also found no significant differences between the young and old heterochronic mice, demonstrating that circulating factors can be a driver of age-related differences in mitochondrial structure and function.

scholarly journals The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

2020 ◽  
Vol 22 (1) ◽  
pp. 91
Author(s):  
Vanina Romanello
Keyword(s):  
Mitochondrial Dysfunction ◽  
Poor Quality ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Mitochondrial Morphology ◽  
Mass Force ◽  
Major Mechanism ◽  
Muscle Aging ◽  
And Function

Sarcopenia is a chronic disease characterized by the progressive loss of skeletal muscle mass, force, and function during aging. It is an emerging public problem associated with poor quality of life, disability, frailty, and high mortality. A decline in mitochondria quality control pathways constitutes a major mechanism driving aging sarcopenia, causing abnormal organelle accumulation over a lifetime. The resulting mitochondrial dysfunction in sarcopenic muscles feedbacks systemically by releasing the myomitokines fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), influencing the whole-body homeostasis and dictating healthy or unhealthy aging. This review describes the principal pathways controlling mitochondrial quality, many of which are potential therapeutic targets against muscle aging, and the connection between mitochondrial dysfunction and the myomitokines FGF21 and GDF15 in the pathogenesis of aging sarcopenia.

scholarly journals Individualized Hemodynamic Management in Sepsis

2021 ◽  
Vol 11 (2) ◽  
pp. 157
Author(s):  
Marcell Virág ◽  
Tamas Leiner ◽  
Mate Rottler ◽  
Klementina Ocskay ◽  
Zsolt Molnar
Keyword(s):  
Fluid Overload ◽  
Fluid Management ◽  
Multiple Organ ◽  
Treatment Protocols ◽  
Hemodynamic Management ◽  
New Approach ◽  
Hemodynamic Optimization ◽  
The Individual ◽  
Sepsis And Septic Shock ◽  
Insight Into

Hemodynamic optimization remains the cornerstone of resuscitation in the treatment of sepsis and septic shock. Delay or inadequate management will inevitably lead to hypoperfusion, tissue hypoxia or edema, and fluid overload, leading eventually to multiple organ failure, seriously affecting outcomes. According to a large international survey (FENICE study), physicians frequently use inadequate indices to guide fluid management in intensive care units. Goal-directed and “restrictive” infusion strategies have been recommended by guidelines over “liberal” approaches for several years. Unfortunately, these “fixed regimen” treatment protocols neglect the patient’s individual needs, and what is shown to be beneficial for a given population may not be so for the individual patient. However, applying multimodal, contextualized, and personalized management could potentially overcome this problem. The aim of this review was to give an insight into the pathophysiological rationale and clinical application of this relatively new approach in the hemodynamic management of septic patients.

Mitochondrial Morphology and Function

Muscle ◽  
2012 ◽  
pp. 217-229
Author(s):  
Fabio Di Lisa ◽  
Luca Scorrano
Keyword(s):  
Mitochondrial Morphology ◽  
And Function
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