Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

Ljubković, Marko; Gressette, Mélanie; Bulat, Cristijan; Ćavar, Marija; Baković, Darija; Fabijanić, Damir; Grković, Ivica; Lemaire, Christophe; Marinović, Jasna

doi:10.2337/db19-0423

Cited by 63 publications

(42 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In experimental diabetic cardiomyopathy, severe ER stress and prolonged UPR ER activation contribute to cardiomyocyte apoptotic death [90,91]. In line, markers of ER stress (GRP78 and CHOP) and apoptosis (cleaved caspase-3) were elevated in myocardium of diabetic patients [92].…”

Section: Alterations Of Interactions Between the Er And Mitochondria mentioning

confidence: 84%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

View full text Add to dashboard Cite

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function. of 15including the ubiquitin-proteasomal system (UPS) and autophagy [9]. In general, cellular stress, including stress caused by cardiac disease, activates multiple stress pathways, including the cytosolic heat shock response, the endoplasmic reticulum (ER) unfolded protein response (UPR ER ), and the mitochondrial UPR (UPR mt ) [10][11][12].Within the PQC, the ER and mitochondria play a critical role in the regulation of protein homeostasis and the maintenance of normal cellular function. The ER is an essential organelle involved in protein synthesis, folding, and trafficking. As protein folding is an error-prone process, the PQC system of the ER is specialized in optimizing this process, thereby preserving cardiac protein quality and homeostasis [13]. As approximately 30% of the cardiomyocyte volume is comprised of mitochondria, the maintenance of a healthy and functional mitochondrial PQC system, which includes molecular chaperones (e.g., HSP60 and HSP10) and proteases (e.g., ClpP), is critical to conserve the energy balance and cardiomyocyte function. The PQC system in mitochondria activates, upon stress, protein folding assistance mechanisms and promotes clearance of misfolded proteins to preserve mitochondrial function [14,15].Thus, a healthy proteostasis in cardiomyocytes safeguards the proper contractile function in the heart. The ER and mitochondria are essential organelles for regulating protein homeostasis, thereby guaranteeing cardiomyocyte function and survival. Therefore, a deeper understanding of ER and mitochondrial function during health and cardiac disease is required to ultimately develop novel therapeutic strategies. Role of the ER in Cardiac HealthThe ER is an essential organelle supporting multiple cellular processes such as protein synthesis, protein folding, regulation of Ca 2+ homeostasis, and contribution to the generation of autophagosomes and peroxisomes [16]. The ER lumen constitutes of a specialized fol...

show abstract

Section: Alterations Of Interactions Between the Er And Mitochondria mentioning

confidence: 84%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…The relative contribution of these lipid intermediates to insulin resistance and altered mitochondrial function remains to be elucidated, and in particular it is not clear whether lipid intermediates accumulate in cardiac tissues at sufficient levels to induce insulin resistance and alter mitochondrial function. It was recently reported, however, that the diabetic heart exhibits a decreased mitochondrial capacity for β‐oxidation and increased accumulation of intracellular lipids, even in the absence of contractile failure . Depending on nutritional status and metabolic state, concentrations of lipid intermediates vary significantly.…”

Section: Pathophysiology Of Disturbances In Mitochondrial Metabolism mentioning

confidence: 99%

“…It was recently reported, however, that the diabetic heart exhibits a decreased mitochondrial capacity for β-oxidation and increased accumulation of intracellular lipids, even in the absence of contractile failure. 85 Depending on nutritional status and metabolic state, concentrations of lipid intermediates vary significantly. The DAG content in control animal hearts varies from 50 to 800 nmol/g.…”

Section: Diacylglycerol-and Ceramideinduced Lipotoxicitymentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

View full text Add to dashboard Cite

Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

show abstract

“…SIRT1 is a highly conserved member of the family of NAD + -dependent Sir2 histone deacetylases (Rodgers et al, 2005) and has also been reported to sense the redox shifts and integrate mitochondrial metabolism through post-transcriptional regulation of the transcription factors and histones (Vachharajani et al, 2016). HADHA and HADHB, respectively, encode the α and β subunits of the mitochondrial trifunctional protein, catalyzing the last three steps of mitochondrial beta-oxidation of long-chain fatty acids (Diebold et al, 2019;Ljubkovic et al, 2019) also observed that in diabetic myocardium, a decrease in HADHA reduces the mitochondrial β-oxidation capacity and increases intracellular lipid accumulation, resulting in a negative impact on the heart. Moreover, Vasilescu et al (2018) demonstrated that HADHB is directly associated with severe childhood-onset cardiomyopathies.…”

Section: Discussionmentioning

confidence: 99%

The Small GTPases Rab27b Regulates Mitochondrial Fatty Acid Oxidative Metabolism of Cardiac Mesenchymal Stem Cells

Jin

Shen

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cardiac mesenchymal stem cells (C-MSCs) are endogenous cardiac stromal cells that play a crucial role in maintaining normal cardiac function. Rab27b is a member of the small GTPase Rab family that controls membrane trafficking and the secretion of exosomes. However, its role in regulating energy metabolism in C-MSC is unclear. In this study, we analyzed mitochondrial oxidative phosphorylation by quantifying cellular oxygen consumption rate (OCR) and quantified the extracellular acidification rate (ECAR) in C-MSC with/without Rab27b knockdown. Knockdown of Rab27b increased glycolysis, but significantly reduced mitochondrial oxidative phosphorylation (OXPHOS) with loss of mitochondrial membrane potential in C-MSC. Furthermore, knockdown of Rab27b reduced H3k4me3 expression in C-MSC and selectively decreased the expression of the essential genes involved in β-oxidation, tricarboxylic acid cycle (TCA), and electron transport chain (ETC). Taken together, our findings highlight a novel role for Rab27b in maintaining fatty acid oxidation in C-MSCs.

show abstract

Disturbed Fatty Acid Oxidation, Endoplasmic Reticulum Stress, and Apoptosis in Left Ventricle of Patients With Type 2 Diabetes

Cited by 63 publications

References 36 publications

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Altered mitochondrial metabolism in the insulin‐resistant heart

The Small GTPases Rab27b Regulates Mitochondrial Fatty Acid Oxidative Metabolism of Cardiac Mesenchymal Stem Cells

Contact Info

Product

Resources

About