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blueoaknx · 3 months ago

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Mitochondrial Dysfunction in Cardiovascular Disease

Introduction

Mitochondria are essential organelles responsible for the production of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The heart, due to its continuous contractile activity, has a high energy demand and is critically dependent on mitochondrial function for normal physiological and pathological processes. Mitochondrial dysfunction has emerged as a central mechanism in the pathogenesis of cardiovascular diseases (CVDs), including ischemic heart disease, heart failure, hypertension, and arrhythmias. This technical overview discusses the molecular mechanisms of mitochondrial dysfunction in cardiovascular disease, its impact on cellular and organ function, and the potential therapeutic strategies to mitigate mitochondrial-related pathophysiology in CVDs.

Mitochondrial Function in Cardiovascular Cells

Mitochondria are highly dynamic organelles that perform several key functions crucial for the health of cardiovascular cells. They are involved in:

ATP Production via Oxidative Phosphorylation: In the mitochondria, energy production is driven by the electron transport chain (ETC), which is composed of complex I-IV embedded in the inner mitochondrial membrane. Electrons derived from NADH and FADH2 produced during the citric acid cycle are transferred through these complexes to ultimately reduce oxygen to water at complex IV. This electron transfer drives proton pumps that create an electrochemical gradient (proton motive force) across the inner mitochondrial membrane, which is utilized by ATP synthase (complex V) to produce ATP.

Calcium Homeostasis: Mitochondria play a crucial role in buffering intracellular calcium concentrations. They take up calcium from the cytoplasm in response to cellular signaling and help maintain cellular homeostasis by storing calcium in the matrix and releasing it when required for cellular signaling. Dysregulation of mitochondrial calcium handling can lead to pathophysiological conditions such as mitochondrial permeability transition (MPT) and cell death.

Reactive Oxygen Species (ROS) Production: Mitochondria are the primary source of ROS due to the incomplete reduction of oxygen molecules during electron transport in the ETC. Under normal conditions, low levels of ROS act as signaling molecules. However, excessive ROS generation due to mitochondrial dysfunction can cause oxidative stress, which damages cellular components such as lipids, proteins, and mitochondrial DNA (mtDNA), contributing to the pathogenesis of cardiovascular diseases.

Apoptosis and Cell Death: Mitochondria are central regulators of apoptosis. The release of pro-apoptotic factors such as cytochrome c from the mitochondrial intermembrane space into the cytoplasm triggers caspase activation, leading to programmed cell death. Mitochondrial dysfunction in cardiovascular tissues can lead to inappropriate cell death, contributing to the progression of CVDs.

Molecular Mechanisms of Mitochondrial Dysfunction in Cardiovascular Disease

Mitochondrial dysfunction in cardiovascular disease can result from several factors, including oxidative damage, altered mitochondrial dynamics, mutations in mitochondrial DNA, and defects in mitochondrial signaling. Below are the primary molecular mechanisms contributing to mitochondrial dysfunction in cardiovascular pathologies:

1. Oxidative Stress and ROS Accumulation

Excessive ROS generation is a hallmark of mitochondrial dysfunction and a major contributor to cardiovascular disease progression. Under normal conditions, the ETC produces ROS as a byproduct of electron transfer; however, under pathological conditions such as ischemia, hypoxia, or heart failure, there is an increase in mitochondrial ROS production. This increase is due to the altered electron flow through the ETC, particularly at complex I and III, which results in the incomplete reduction of oxygen.

The accumulation of ROS causes oxidative damage to mitochondrial lipids, proteins, and mtDNA. For instance, lipid peroxidation of mitochondrial membranes leads to membrane destabilization and disruption of mitochondrial function. ROS also modify proteins involved in mitochondrial dynamics and bioenergetics, impairing the capacity of mitochondria to generate ATP. Furthermore, oxidative damage to mtDNA leads to mutations that compromise the mitochondrial respiratory chain complexes, creating a vicious cycle of mitochondrial dysfunction.

2. Mitochondrial Permeability Transition (MPT) and Calcium Overload

Mitochondrial permeability transition is a critical event in mitochondrial dysfunction. The opening of the mitochondrial permeability transition pore (mPTP) occurs when the inner mitochondrial membrane becomes permeable to ions and small molecules, disrupting the electrochemical gradient required for ATP production. Under pathological conditions such as ischemia-reperfusion injury, excessive ROS and calcium overload activate the mPTP, leading to mitochondrial swelling, loss of membrane potential, and the release of pro-apoptotic factors (e.g., cytochrome c), triggering cell death.

Calcium overload plays a significant role in mitochondrial dysfunction. During stress conditions like ischemia, excessive intracellular calcium is taken up by mitochondria, causing mitochondrial matrix expansion and rupture of the mitochondrial membrane. This exacerbates cellular injury and promotes cell death pathways in the myocardium, contributing to myocardial infarction and heart failure.

3. Mitochondrial Dynamics Dysregulation

Mitochondrial dynamics refer to the continuous processes of mitochondrial fusion and fission that maintain mitochondrial quality and function. In response to cellular stress, mitochondria can undergo fission to segregate damaged components or fusion to promote functional compensation. Mitochondrial fission is regulated by dynamin-related protein 1 (DRP1), while fusion is mediated by mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1). In cardiovascular diseases, this dynamic balance is often disrupted, leading to mitochondrial fragmentation, reduced mitochondrial function, and increased susceptibility to apoptosis.

In heart failure, for example, the upregulation of DRP1 and downregulation of fusion proteins contribute to mitochondrial fragmentation, reduced ATP production, and elevated ROS levels. This dysfunction is exacerbated by altered signaling pathways, including those associated with autophagy (mitophagy), which is responsible for removing damaged mitochondria. Dysfunctional mitophagy further impairs mitochondrial quality control, worsening cardiac injury.

4. Mitochondrial DNA Mutations

Mitochondrial DNA is more prone to mutations than nuclear DNA due to its proximity to the ETC and lack of protective histones. In cardiovascular diseases, mutations in mtDNA contribute to defective mitochondrial function. For example, mutations in genes encoding subunits of the OXPHOS complexes (such as ATP6, ND1, or CYTB) lead to impaired ATP synthesis and defective mitochondrial bioenergetics, contributing to myocardial ischemia and heart failure.

Mitochondrial mutations may also affect the regulation of ROS production and the activation of apoptotic pathways, accelerating tissue damage and organ dysfunction.

Therapeutic Approaches Targeting Mitochondrial Dysfunction in Cardiovascular Disease

Given the critical role of mitochondria in cardiovascular disease, several therapeutic strategies have been developed to target mitochondrial dysfunction and restore normal mitochondrial function. These include:

1. Mitochondrial Antioxidants

Mitochondrial-targeted antioxidants, such as MitoQ, MitoTEMPO, and SkQ1, have been developed to specifically target ROS within mitochondria. These compounds aim to reduce oxidative stress, limit mitochondrial damage, and improve mitochondrial function. Clinical studies are ongoing to assess the efficacy of these antioxidants in reducing myocardial injury and improving outcomes in heart failure and ischemic heart disease.

2. Mitochondrial Biogenesis Activation

Stimulating mitochondrial biogenesis to increase the number of functional mitochondria is another potential therapeutic strategy. Activators of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis, are being investigated as potential treatments for heart failure. Exercise training is a natural way to activate PGC-1α and increase mitochondrial function, which has been shown to improve cardiac outcomes in patients with heart failure.

3. MPTP Inhibition

Inhibitors of the mPTP, such as cyclosporine A, have been studied for their potential to prevent ischemia-reperfusion injury by inhibiting pore opening. By preserving mitochondrial integrity, these inhibitors may help reduce myocardial damage and improve survival after myocardial infarction.

4. Gene Therapy and Mitochondrial Transplantation

Gene therapy approaches, including the use of CRISPR/Cas9 to correct mitochondrial DNA mutations, hold promise in treating mitochondrial diseases. Additionally, mitochondrial transplantation, where healthy mitochondria are delivered to damaged cardiac cells, is an emerging area of research, with the potential to restore mitochondrial function and improve heart function in patients with severe myocardial injury.

Conclusion

Mitochondrial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, contributing to impaired ATP production, increased ROS production, and cell death. Understanding the molecular mechanisms underlying mitochondrial dysfunction provides critical insights into the development of novel therapeutic strategies. Approaches targeting mitochondrial biogenesis, oxidative stress, mitochondrial dynamics, and mPTP inhibition offer promising avenues for the treatment of cardiovascular diseases and could lead to more effective management of conditions such as heart failure, ischemic heart disease, and hypertension. However, further research and clinical trials are needed to fully elucidate the potential of these therapeutic strategies in improving cardiovascular health.

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healthtimetaylor · 5 years ago

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Aged garlic extract and its constituent, S-allyl-L-cysteine, induce the apoptosis of neuroblastoma cancer cells

PMID: Exp Ther Med. 2020 Feb ;19(2):1511-1521. Epub 2019 Dec 27. PMID: 32010332 Abstract Title: Aged garlic extract and its constituent, S-allyl-L-cysteine, induce the apoptosis of neuroblastoma cancer cells due to mitochondrial membrane depolarization. Abstract: Aged garlic extract (AGE) has been demonstrated to have therapeutic properties in tumors; however its mechanisms of action have not yet been fully elucidated. A previous study revealed that AGE exerts an anti-proliferative effect on a panel of both sensitive [wild-type (WT)] and multidrug-resistant (MDR) human cancer cells. Following treatment of the cells with AGE, cytofluorimetric analysis revealed the occurrence of dose-dependent mitochondrial membrane depolarization (MMD). In this study, in order to further clarify the mechanisms of action of AGE, the effects of AGE on mitochondria isolated from rat liver mitochondria (RLM) were also examined. AGE induced an effect on the components of the electrochemical gradient (Δµ), mitochondrial membrane potential (ΔΨ) and mitochondrial electrochemical gradient (ΔpH). The mitochondrial membrane dysfunctions of RLM induced by AGE, namely the decrease in both membrane potential and chemical gradient were associated with a higher oxidation of both the endogenous glutathione and pyridine nucleotide content. To confirm the anti-proliferative effects of AGE, experiments were performed on the human neuroblastoma (NB) cancer cells, SJ-N-KP and the MYCN-amplified IMR5 cells, using its derivative S-allyl-L-cysteine (SAC), with the aim of providing evidence of the anticancer activity of this compound and its possible molecular mechanism as regards the induction of cytotoxicity. Following treatment of the cells with SAC at 20 mM, cell viability was determined by MTT assay and apoptosis was detected by flow cytometry, using Annexin V-FITC labeling. The percentages of cells undergoing apoptosis was found to be 48.0% in the SJ-N-KP and 50.1% in the IMR5 cells. By cytofluorimetric analysis, it was suggested that the target of SAC are the mitochondria. Mitochondrial activity was examined by labeling the cells with the probe, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylimidacarbocyanine iodide (JC-1). Following treatment with SAC at 50 mM, both NB cell lines exhibited a marked increase in MMD. On the whole, the findings of this study indicate that both natural products, AGE and SAC, cause cytotoxicity to tumor cells via the induction of mitochondrial permeability transition (MPT).

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lopezdorothy70-blog · 7 years ago

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Blue light exposure can induce damages to human retinal pigment epithelium cells in vitro

PMID: Zhonghua Yan Ke Za Zhi. 2006 Dec ;42(12):1095-102. PMID: 17415967 Abstract Title: [Relationship between blue light-induced apoptosis and mitochondrial membrane potential and cytochrome C in cultured human retinal pigment epithelium cells]. Abstract: OBJECTIVE: To investigate the effect of blue light on apoptosis and mitochondrial permeability transition (MPT) of cultured human retinal pigment epithelium (RPE) cells in vitro.METHODS: Human RPE cells were exposed to blue light (wave length 470 -490 nm). The present study consisted of three parts. Part one studied the effect of various intensities of blue light on the RPE cells. Cells were irradiated with (500+/-100) lx (group 1) , (2000+/-500) lx (group 2) and (3000+/-500)lx ( group 3) blue light, and followed by 24 hours observation. Part two studied the effect of various duration of blue light at identical intensity on the RPE cells. For the study on various subtypes of RPE cells, cells were irradiated by blue light at (2000+/-500) x for 6, 12, and 24 hours. For the study of mitochondrial membrane potential, cells were irradiated for 3, 6, and 12 hours. Part three studied cells irradiated with blue light at identical intensity and duration, but with various prolongation of post-exposure culture. The prolongation of post-exposure culture was 6, 12, 24, and 36 hours. Phototoxicity was quantified at various periods after exposure by staining of the nuclei of membrane-compromised cells, by TdT-dUTP terminal nick-end labeling (TUNEL) of apoptotic cells and by Annexin V labeling for phosphatidylserine exposure. Transmission electronmicroscopy was used to determine the ultrastructure changes of RPE cells. Mitochondrial membrane potential ( deltaPsim ) was measured by rhodamine 123 staining and subsequent flow cytometry. Cytochrome C activity was assayed by ELISA. Caspase-3 was detected by colorimetric assay.RESULTS: TUNEL-positive labeling cells in first group of part two study showed cell shrinkage, membrane blebbing, apoptotic body, condensation and fragmentation of chromatin. Mitochondrial swelling, extinction of inner mitochondrial membrane ridge, dilation of rough endoplasmic reticulum and increase of the lysosome were also observed in transmission electronmicroscopy. Blue light at (500 +/- 100) x intensity did not induce damage to RPE cells, but decrease of delta Psim was observed. A significant increase of apoptotic, apoptotic necrotic and necrotic percentages, as well as significant decrease of deltaPsim were observed at higher light intensity in part one study. Increase of apoptotic percentage was the main response to shorter exposure of blue light. Increase of apoptotic necrotic and necrotic percentage and pronounced decrease of deltaPsim occurred in cells irradiated by longer exposure in part two study. In part 3 study, apoptotic response was increased gradually during 6 and 12 hours prolongation of post-exposure culture, more apoptotic necrosis or necrosis were found after post-exposure 24 hours. Decrease of deltaPsim was observed in 6 hours prolongation of post-exposure culture and lasting for 48 hours. The concentration of cytochrome C was significantly increased in post-exposure 24 and 36 hours, without any changes of Caspase-3 activity.CONCLUSIONS: Blue light exposure can induce damages to human RPE cells in vitro, which include apoptosis, apoptotic necrosis and necrosis. These changes are caused by triggering the mitochondrial permeability transition, which results in decrease of deltaPsim and release of cytochrome C. deltaPsim can be used as a earlier parameter of blue light-induced apoptosis.

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battybat-boss · 7 years ago

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Blue light exposure can induce damages to human retinal pigment epithelium cells in vitro

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