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Mitochondria oxidative stress in ischemic heart disease. Mitochondria is the main source of ROS, after oxidative stress, the respiratory chain could generate ROS, the imbalance level of ROS could attribute to mtDNA damage, initiate the open of mPTP, leading to cell death.
Source publication
IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention...
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Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, there...
Citations
... Mitochondria form a dynamic network that moderates their quantity and quality to maintain mitochondrial function. This is achieved through processes such as mitochondrial fusion, fission, mitophagy, biogenesis and protein homeostasis [6][7][8]. Studies have demonstrated the significance of mitochondrial dynamics and mitophagy in cardiovascular disease, including AMI [9][10][11]. In mammalian cells, mitochondrial dynamin-related protein 1 (Drp1) primarily regulates mitochondrial division, while optic atrophy 1 (Opa1) controls mitochondrial fusion [12]. ...
Background
Rhein, which has antioxidant and anti-inflammatory response properties, is a beneficial treatment for different pathologies. However, the mechanism by which rhein protects against myocardial ischemic injury is poorly understood.
Methods and results
To establish an acute myocardial infarction (AMI) rat model, we performed left anterior descending (LAD) ligation. Sprague‒Dawley rats were randomly divided into four groups: sham, AMI, AMI + rhein (AMI + R), and AMI + mitochondrial fission inhibitor (AMI + M). The extent of myocardial injury was evaluated by TTC staining, serum myocardial injury markers, and HE and Masson staining. Cardiac mitochondria ultrastructure was visualized by transmission electron microscopy. TUNEL assay and flow cytometry analysis were used to estimate cell apoptosis. Protein expression levels were measured by Western blotting. In vitro, the efficacy of rhein was assessed in H9c2 cells under hypoxic condition. Our results revealed that rats with AMI exhibited increased infarct size and indicators of myocardial damage, along with activation of Drp1-dependent mitochondrial fission, decreased mitophagy and increased apoptosis rates. However, pretreatment with rhein significantly reversed these effects and demonstrated similar efficacy to Mdivi-1. Furthermore, rhein pretreatment protected against myocardial ischemic injury by inhibiting mitochondrial fission, as evidenced by decreased Drp1 expression. It also enhanced mitophagy, as indicated by increased expression of Beclin1, Pink1 and Parkin, an increased LC3-II/LC3-I ratio and increased formation of autolysosomes. Additionally, rhein pretreatment mitigated apoptosis in AMI. These results were also confirmed in vitro in H9c2 cells.
Conclusion
Our results demonstrate that rhein pretreatment exerts cardioprotective effects against myocardial ischemic injury via the Drp1/Pink1/Parkin pathway.
... Mitochondria are the primary source of ROS. After myocardial ischemia, the mitochondrial oxidative respiratory chain produces ROS, and the ROS level imbalance initiates the opening of MPTP [46]. Moreover, omentin could inhibit DOX-induced cardiac apoptosis by reducing mitochondrial ROS production [47]. ...
Ginsenoside Rd is an active ingredient in Panax ginseng CA Mey and can be absorbed into the adipose tissue. Adipokines play an important role in the treatment of cardiovascular diseases. However, the potential benefit of Rd on heart failure (HF) and the underlying mechanism associated with the crosstalk between adipocytes and cardiomyocytes remains to be illustrated. Here, the results identified that Rd improved cardiac function and inhibited cardiac pathological changes in transverse aortic constriction (TAC), coronary ligation (CAL) and isoproterenol (ISO)-induced HF mice. And Rd promoted the release of omentin from the adipose tissue and up-regulated omentin expression in lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes. Further, Rd could increase TBK1 and AMPK phosphorylation in adipocytes. And also, the TBK1-AMPK signaling pathway regulated the expression of omentin in LPS-induced adipocytes. Moreover, the omentin mRNA expression was significantly decreased by TBK1 knockdown in LPS-induced 3T3-L1 adipocytes. Additionally, molecular docking and SPR analysis confirmed that Rd had a certain binding ability with TBK1, and co-treatment with TBK1 inhibitors or TBK1 knockdown partially abolished the effect of Rd on increasing the omentin expression and the ratio of p-AMPK to AMPK in adipocytes. Moreover, we found that circulating omentin level diminished in the HF patients compared with healthy subjects. Meanwhile, the adipose tissue-specific overexpression of omentin improved cardiac function, reduced myocardial infarct size and ameliorated cardiac pathological features in CAL-induced HF mice. Consistently, exogenous omentin reduced mtROS levels and restored ΔψM to improve oxygen and glucose deprivation (OGD)-induced cardiomyocytes injury. Further, omentin inhibited the WNT5A/Ca²⁺ signaling pathway and promoted mitochondrial biogenesis function to ameliorate myocardial ischemia injury. However, WNT5A knockdown inhibited the impairment of mitochondrial biogenesis and partially counteracted the cardioprotective effect of omentin in vitro. Therefore, this study indicated that Rd promoted omentin secretion from adipocytes through the TBK1-AMPK pathway to improve mitochondrial biogenesis function via WNT5A/Ca²⁺ signaling pathway to ameliorate myocardial ischemia injury, which provided a new therapeutic mechanism and potential drugs for the treatment of HF.
... Mitochondria are highly dynamic, and are involved in many processes, including apoptosis, cell cycle, intracellular Ca 2+ (Calcium) homeostasis, Cell differentiation, Oxidative stress (28,29,(32)(33)(34)(35). In cardiomyocytes, mitochondria have a high density and their main role is to produce ATP, which is accomplished through respiratory metabolism and oxidative phosphorylation. ...
Background:
Diabetes can increase the risk of coronary heart disease, and also increase the mortality rate of coronary heart disease in diabetic patients. Although reperfusion therapy can preserve the viable myocardium, fatal reperfusion injury can also occur. Studies have shown that diabetes can aggravate myocardial ischemia-reperfusion injury, ERK1/2 can reduce myocardial ischemia-reperfusion injury, but its mechanism in hyperglycemic myocardial ischemia-reperfusion injury is unclear. This study sought to explore the mechanism of extracellular signal-regulated kinase 1/2 (ERK1/2) in hyperglycemic myocardial ischemia reperfusion (I/R) injury.
Methods:
H9C2 cardiomyocytes were treated with high-glucose (HG) medium plus I/R stimulation to establish a hyperglycemia I/R model in vitro. The cells were treated with LM22B-10 (an ERK activator) or transfected with the constitutive activation of the mitogen-activated protein kinase 1 (CaMEK) gene. Myocardial cell apoptosis, mitochondria functional-related indicators, the oxidative stress indexes, and the expression levels of ERK1/2 protein were detected.
Results:
The HG I/R injury intervention caused an increase in the ratio of apoptotic cardiomyocytes (P<0.05), but the phosphorylation level of the ERK1/2 protein did not increase further. Administering LM22B-10 or transfecting the CaMEK gene significantly activated the phosphorylation levels of ERK1/2 protein and reduced the proportion of cardiomyocyte apoptosis (P<0.05). HG I/R injury increased mitochondrial fission and reduced membrane potential. The intervention reduced the number of punctate mitochondria, increased the average network structure size and median branch length (P<0.01), increased the median network structure size and average branch length (P<0.05), and reduced the colocalization of Drp1 (Dynamin-Related protein1)/TOMM20 (Mitochondrial outer membrane translocation enzyme 20) (P<0.05) and Drp1 with serine 616 phosphorylation (Drp1s616) phosphorylation (P<0.01), thereby reducing mitochondrial fission, increasing membrane potential and mitochondrial function. HG I/R injury increased the level of oxidative stress, while administering LM22B-10 or transfecting the CaMEK gene reduced the level of oxidative stress (P<0.01).
Conclusions:
Targeting the activation of ERK1/2 protein phosphorylation reduced mitochondrial fission, increased membrane potential and mitochondrial function, reduced oxidative stress and myocardial cell apoptosis, and alleviated hyperglycemia myocardial I/R injury.
... Mitophagy plays a vital role in the balance of mitochondrial dynamics and the balance of mitochondrial fission, and fusion is closely correlated to maintaining mitochondrial homeostasis, cell stability and cell survival [59] . The mitochondrial fission process includes mitochondrial contraction and division, while the mitochondrial fusion process includes mitochondrial joining and tethering. ...
Ischemic stroke is a serious cerebrovascular disease with high morbidity and mortality. As a result of ischemia-reperfusion, a cascade of pathophysiological responses is triggered by the imbalance in metabolic supply and demand, resulting in cell loss. These cellular injuries follow various molecular mechanisms solely or in combination with this disorder. Mitochondria play a driving role in the pathophysiological processes of ischemic stroke. Once ischemic stroke occurs, damaged cells would respond to such stress through mitophagy. Mitophagy is known as a conservatively selective autophagy, contributing to the removal of excessive protein aggregates and damaged intracellular components, as well as aging mitochondria. Moderate mitophagy may exert neuroprotection against stroke. Several pathways associated with the mitochondrial network collectively contribute to recovering the homeostasis of the neurovascular unit. However, excessive mitophagy would also promote ischemia-reperfusion injury. Therefore, mitophagy is a double-edged sword, which suggests that maximizing the benefits of mitophagy is one of the direction of future efforts. This review emphasized the role of mitophagy in ischemic stroke, and highlighted the crosstalk between mitophagy and apoptosis/necroptosis.
... Mitophagy plays a vital role in the balance of mitochondrial dynamics and the balance of mitochondrial fission, and fusion is closely correlated to maintaining mitochondrial homeostasis, cell stability and cell survival [59] . The mitochondrial fission process includes mitochondrial contraction and division, while the mitochondrial fusion process includes mitochondrial joining and tethering. ...
Ischemic stroke is a serious cerebrovascular disease with high morbidity and mortality. As a result of ischemia-reperfusion, a cascade of pathophysiological responses is triggered by the imbalance in metabolic supply and demand, resulting in cell loss. These cellular injuries follow various molecular mechanisms solely or in combination with this disorder. Mitochondria play a driving role in the pathophysiological processes of ischemic stroke. Once ischemic stroke occurs, damaged cells would respond to such stress through mitophagy. Mitophagy is known as a conservatively selective autophagy, contributing to the removal of excessive protein aggregates and damaged intracellular components, as well as aging mitochondria. Moderate mitophagy may exert neuroprotection against stroke. Several pathways associated with the mitochondrial network collectively contribute to recovering the homeostasis of the neurovascular unit. However, excessive mitophagy would also promote ischemia-reperfusion injury. Therefore, mitophagy is a double-edged sword, which suggests that maximizing the benefits of mitophagy is one of the direction of future efforts. This review emphasized the role of mitophagy in ischemic stroke, and highlighted the crosstalk between mitophagy and apoptosis/necroptosis.
... Interventional coronary reperfusion strategies are widely adopted to treat acute myocardial infarction, and initiation of cardiac remodeling treatment within 24 hours of hospitalization has been a standard procedure in the management of acute coronary syndrome, but the morbidity and mortality due to acute myocardial infarction and ischemic cardiomyopathy are still high [3][4][5][6].The identification of MI onset is crucial for timely intervention, subsequently helpful for reducing these adverse events. One characteristic of the chronic stage of ischemic heart disease is maladaptive myocardial remodeling [7], manifested as cardiomyocyte hypertrophy and death, extracellular matrix deposition (including fibrosis), and immune and inflammation injuries [8]. Although mounting studies focused on the underlying mechanisms of this pathological process, there are still gaps in our understanding of myocardial remodeling, and there are no effective strategies to reverse this process. ...
... Mitochondrion homeostasis is crucial to cardiac metabolism and contraction [12]. Studies have shown that mitochondrial structure and metabolism remodeling are key characteristics of MI [7]. For instance, mitochondrial apoptosis and disrupted fission and fusion exacerbated cardiac ischemia-reperfusion injury in mouse [13,14]; disturbed mitochondrial dynamics was involved in cardiac microcirculation in ischemia-reperfusion injury and myocardial infarction [15][16][17][18][19]. Thousands of studies have presented mitochondrial metabolism profiles in ischemia-reperfusion injury [20][21][22][23][24] and acute myocardial infraction hearts, and have screened thousands of potential biomarkers of these processes [25][26][27][28]. ...
Cardiac remodeling is the primary pathological feature of chronic heart failure. Prompt inhibition of remodeling in acute coronary syndrome has been a standard procedure, but the morbidity and mortality are still high. Exploring the characteristics of ischemia in much earlier stages and identifying its biomarkers are essential for introducing novel mechanisms and therapeutic strategies. Metabolic and structural remodeling of mitochondrion is identified to play key roles in ischemic heart disease. The mitochondrial metabolic features in early ischemia have not previously been described. In the present study, we established a mouse heart in early ischemia and explored the mitochondrial metabolic profile using metabolomics analysis. We also discussed the role of mitochondrion in the global cardiac metabolism. Transmission electron microscopy revealed that mitochondrial structural injury was invoked at 8 minutes post-coronary occlusion. In total, 75 metabolites in myocardium and 26 in mitochondria were screened out. About 23% of the differentiated metabolites in mitochondria overlapped with the differentiated metabolites in myocardium; Total 81% of the perturbed metabolic pathway in mitochondria overlapped with the perturbed pathway in myocardium, and these pathways accounted for 50% of the perturbed pathway in myocardium. Purine metabolism was striking and mechanically important. In conclusion, in the early ischemia, myocardium exacerbated metabolic remodeling. Mitochondrion was a contributor to the myocardial metabolic disorder. Purine metabolism may be a potential biomarker for early ischemia diagnosis. Our study introduced a perspective for prompt identification of ischemia.
Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
Mitochondrial protein sequence similarity 3 gene family member A (FAM3A) plays important roles in the electron transfer chain, while its functions in the heart are still unknown. This study aims to explore the roles and mechanisms of FAM3A after myocardial infarction (MI). FAM3A-deficient (Fam3a−/−) mice were implemented with MI injury and showed lower survival rates at 4 weeks as well as decreased cardiac systolic function. Isolated cardiomyocytes of Fam3a−/− mice showed reduced basal, ATP-linked respiration and respiratory reserve compared to that of wild-type mice. Transmission electron microscopy studies showed Fam3a−/− mice had a larger size and elevated density of mitochondria. FAM3A deficiency also induced elevated mitochondrial Ca²⁺, higher opening level of mPTP, lower mitochondrial membrane potential and elevated apoptotic rates. Further analyses demonstrated that mitochondrial dynamics protein Opa1 contributed to the effects of FAM3A in cardiomyocytes. Our study discloses the important roles of mitochondrial protein FAM3A in the heart.
Graphical abstract
A circadian alteration, as shown by a disturbed sleep and a low-degree inflammation, i.e., “inflammaging,” are two common disruptions oftenly seen in aging. Their aggravation contributes substantially to the etiology of non-communicable diseases (NCDs) like cardiovascular, respiratory and renal disorders, diabetes and the metabolic syndrome, cancer, and neurodegenerative diseases, of a high incidence in the elder population. A common observation in aging is a decline in plasma melatonin, a chemical with extraordinary phylogenetic conservation found in all known aerobic creatures. Every day, the melatonin surge in the late afternoon/early evening synchronizes both the central circadian pacemaker in the hypothalamic suprachiasmatic nuclei and a slew of peripheral cellular clocks (“chronobiotic effect”). Indeed, melatonin is the prototype of the endogenous family of chronobiotic agents. Several meta-analyses and consensus studies back melatonin treatment for sleep/wake cycle disturbance associated with NCDs in the elderly. Melatonin exerts also a cytoprotective action, buffering free radicals and reversing inflammaging by down-regulating pro-inflammatory cytokines, suppressing low-grade inflammation, and preventing insulin resistance, among other effects. Such a versatile activity explains melatonin´s conservation in phylogeny. Melatonin treatment of aged animals prevents a wide range of senescence-related alterations. Circulating melatonin levels are consistently reduced in NCDs. As a result, melatonin's therapeutic efficacy as a chronobiotic/cytoprotective drug that promotes healthy aging should be explored. Sirtuins 1 and 3 are at the heart of melatonin’s chronobiotic and cytoprotective function in healthy aging, with properties such as aging suppressors and mitochondrial protection, as well as accessory components or downstream elements of circadian oscillators. However, allometric calculations based on animal research reveal that the cytoprotective benefits of melatonin require greater doses (in the 100 mg/day range) to become visible. If melatonin is predicted to be successful in improving health, particularly in the elderly, the modest amounts frequently utilized clinically (i.e., 2–10 mg) are unlikely to be beneficial. To examine and further investigate the potential and utility of melatonin in healthy aging, multicenter double-blind studies are required. The melatonin levels employed should be re-evaluated considering preclinical research available.
Background
Mitochondria are remarkably dynamic organelles encapsulated by bilayer membranes. The dynamic properties of mitochondria are critical for energy production.
Aims
The aim of our study is to investigate the global status and trends of mitochondrial dynamics research and predict popular topics and directions in the field.
Methods
Publications related to the studies of mitochondrial dynamics from 2002 to 2021 were retrieved from Web of Science database. A total of 4,576 publications were included. Bibliometric analysis was conducted by visualization of similarities viewer and GraphPadPrism 5 software.
Results
There is an increasing trend of mitochondrial dynamics research during the last 20 years. The cumulative number of publications about mitochondrial dynamics research followed the logistic growth model f(x)=a/1+e(b-cx)\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm{f}(x)=\mathrm{a}/\left[1+{e}^{(b-cx)}\right]$$\end{document}. The USA made the highest contributions to the global research. The journal Biochimica et Biophysica Acta (BBA)—Molecular Cell Research had the largest publication numbers. Case Western Reserve University is the most contributive institution. The main research orientation and funding agency were cell biology and HHS. All keywords related studies could be divided into three clusters: “Related disease research”, “Mechanism research” and “Cell metabolism research”.
Conclusions
Attention should be drawn to the latest popular research and more efforts will be put into mechanistic research, which may inspire new clinical treatments for the associated diseases.
