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Frontiers in Pharmacology 2022Osteoarthritis is a common age-related joint degenerative disease. Pain, swelling, brief morning stiffness, and functional limitations are its main characteristics.... (Review)
Review
Osteoarthritis is a common age-related joint degenerative disease. Pain, swelling, brief morning stiffness, and functional limitations are its main characteristics. There are still no well-established strategies to cure osteoarthritis. Therefore, better clarification of mechanisms associated with the onset and progression of osteoarthritis is critical to provide a theoretical basis for the establishment of novel preventive and therapeutic strategies. Chondrocytes exist in a hypoxic environment, and HIF-1α plays a vital role in regulating hypoxic response. HIF-1α responds to cellular oxygenation decreases in tissue regulating survival and growth arrest of chondrocytes. The activation of HIF-1α could regulate autophagy and apoptosis of chondrocytes, decrease inflammatory cytokine synthesis, and regulate the chondrocyte extracellular matrix environment. Moreover, it could maintain the chondrogenic phenotype that regulates glycolysis and the mitochondrial function of osteoarthritis, resulting in a denser collagen matrix that delays cartilage degradation. Thus, HIF-1α is likely to be a crucial therapeutic target for osteoarthritis regulating chondrocyte inflammation and metabolism. In this review, we summarize the mechanism of hypoxia in the pathogenic mechanisms of osteoarthritis, and focus on a series of therapeutic treatments targeting HIF-1α for osteoarthritis. Further clarification of the regulatory mechanisms of HIF-1α in osteoarthritis may provide more useful clues to developing novel osteoarthritis treatment strategies.
PubMed: 35865944
DOI: 10.3389/fphar.2022.927126 -
International Journal of Biological... 2023Apigenin is the active ingredient in Ludangshen. Although previous studies reported the cardioprotective actions of apigenin against doxorubicin (Dox)-induced...
Apigenin is the active ingredient in Ludangshen. Although previous studies reported the cardioprotective actions of apigenin against doxorubicin (Dox)-induced cardiomyopathy, the underlying mechanisms remain incompletely understood. Since apigenin beneficially regulates various aspects of mitochondrial function and dynamics, we asked whether apigenin improves heart function in mice with Dox-induced cardiomyopathy by regulating the mitochondrial unfolded protein response (UPR). Co-administration of apigenin significantly restored heart function, reduced myocardial swelling, inhibited cardiac inflammation, increased cardiac transcription of UPR-related genes, and promoted cardiomyocyte survival in Dox-treated mice. In turn, blockade of UPR abolished the mito- and cytoprotective effects of apigenin, evidenced by decreased ATP production, suppressed mitochondrial antioxidant capacity, and increased apoptosis, in Dox-treated, cultured HL-1 cardiomyocytes. Furthermore, apigenin treatment prevented Dox-induced downregulation of Sirt1 and Atf5 expression, and the beneficial effects of apigenin were completely nullified in knockout (KO) mice or after siRNA-mediated knockdown . We thus provide novel evidence for a promotive effect of apigenin on UPR via regulation of the Sirt1/Atf5 pathway. Our findings uncover that apigenin seems to be an effective therapeutic agent to alleviate Dox-mediated cardiotoxicity.
Topics: Mice; Animals; Apigenin; Sirtuin 1; Myocytes, Cardiac; Cardiotoxicity; Cardiomyopathies; Mice, Knockout; Doxorubicin; Apoptosis; Oxidative Stress
PubMed: 37928261
DOI: 10.7150/ijbs.85204 -
Cells Jan 2022Alzheimer's disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation,...
Alzheimer's disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ and Aβ in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ and Aβ are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ had more adverse effects than Aβ on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ and Aβ significantly increased Ca -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Endothelial Cells; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Rats
PubMed: 35159183
DOI: 10.3390/cells11030373 -
Investigative Ophthalmology & Visual... Nov 2023Endoplasmic reticulum (ER) and mitochondrial stress are independently associated with corneal endothelial cell (CEnC) loss in many corneal diseases, including Fuchs'...
PURPOSE
Endoplasmic reticulum (ER) and mitochondrial stress are independently associated with corneal endothelial cell (CEnC) loss in many corneal diseases, including Fuchs' endothelial corneal dystrophy (FECD). However, the role of ER stress in mitochondrial dysfunction contributing to CEnC apoptosis is unknown. The purpose of this study is to explore the crosstalk between ER and mitochondrial stress in CEnC.
METHODS
Human corneal endothelial cell line (HCEnC-21T) and human corneal endothelial tissues were treated with ER stressor tunicamycin. ER stress-reducing chemical 4-phenyl butyric acid (4-PBA) was used in HCEnC-21T after tunicamycin. Fuchs' corneal endothelial cell line (F35T) was used to determine differential activation of ER stress with respect to HCEnC-21T at the baseline. ER stress, mitochondrial-mediated intrinsic apoptotic, mitochondrial fission, and fusion proteins were determined using immunoblotting and immunohistochemistry. Mitochondrial bioenergetics were assessed by mitochondrial membrane potential (MMP) loss and ATP production at 48 hours after tunicamycin. Mitochondria dynamics (shape, area, perimeter) were also analyzed at 24 hours using transmission electron microscopy.
RESULTS
Treatment of HCEnC-21T cell line with tunicamycin activated three ER stress pathways (PERK-eIF2α-CHOP, IRE1α-XBP1, and ATF6), reduced cell viability, upregulated mitochondrial-mediated intrinsic apoptotic molecules (cleaved caspase 9, caspase 3, PARP, Bax, cytochrome C), downregulated anti-apoptotic Bcl-2 protein, initiated mitochondrial dysfunction by loss of MMP and lowering of ATP production, and caused mitochondrial swelling and fragmentation with increased expression of mitochondrial fission proteins (Fis1 and p-Drp1). Fuchs' CEnC (F35T) cell line also showed activation of the ER stress-related proteins (p-eIF2α, GRP78, CHOP, XBP1) compared to HCEnC-21T at the baseline. The 4-PBA ameliorated cell loss and reduced cleaved caspase 3 and 9, thereby rescuing tunicamycin-induced cell death but not mitochondrial bioenergetics in HCEnC-21T cell line.
CONCLUSIONS
Tunicamycin-induced ER stress disrupts mitochondrial bioenegetics, dynamics and contributes to the loss of CEnC viability. This novel study highlights the importance of ER-mitochondria crosstalk and its contribution to CEnCs apoptosis, seen in many corneal diseases, including FECD.
Topics: Humans; Caspase 3; Endoribonucleases; Tunicamycin; Protein Serine-Threonine Kinases; Apoptosis; Endoplasmic Reticulum Stress; Corneal Diseases; Fuchs' Endothelial Dystrophy; Butyric Acid; Energy Metabolism; Endothelial Cells; Adenosine Triphosphate
PubMed: 37962528
DOI: 10.1167/iovs.64.14.18 -
Frontiers in Endocrinology 2023Clinical studies have shown that low levels of endogenous testosterone are associated with cardiovascular diseases. Considering the intimate connection between oxidative...
INTRODUCTION
Clinical studies have shown that low levels of endogenous testosterone are associated with cardiovascular diseases. Considering the intimate connection between oxidative metabolism and myocardial contractility, we determined the effects of testosterone deficiency on the two spatially distinct subpopulations of cardiac mitochondria, subsarcolemmal (SSM) and interfibrillar (IFM).
METHODS
We assessed cardiac function and cardiac mitochondria structure of SSM and IFM after 12 weeks of testosterone deficiency in male Wistar rats.
RESULTS AND DISCUSSION
Results show that low testosterone reduced myocardial contractility. Orchidectomy increased total left ventricular mitochondrial protein in the SSM, but not in IFM. The membrane potential, size and internal complexity in the IFM after orchidectomy were higher compared to the SHAM group. However, the rate of oxidative phosphorylation with all substrates in the IFM after orchidectomy was lower compared to the SHAM group. Testosterone replacement restored these changes. In the testosterone-deficient SSM group, oxidative phosphorylation was decreased with palmitoyl-L-carnitine as substrate; however, the mitochondrial calcium retention capacity in IFM was increased. There was no difference in swelling of the mitochondria in either group. These changes in IFM were followed by a reduction in phosphorylated form of AMP-activated protein kinase (p-AMPK-α), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) translocation to mitochondria and decreased mitochondrial transcription factor A (TFAM). Testosterone deficiency increased NADPH oxidase (NOX), angiotensin converting enzyme (ACE) protein expression and reduced mitochondrial antioxidant proteins such as manganese superoxide dismutase (Mn-SOD) and catalase in the IFM. Treatment with apocynin (1.5 mM in drinking water) normalized myocardial contractility and interfibrillar mitochondrial function in the testosterone depleted animals. In conclusion, our findings demonstrate that testosterone deficiency leads to reduced myocardial contractility and impaired cardiac interfibrillar mitochondrial function. Our data suggest the involvement of reactive oxygen species, with a possibility of NOX as an enzymatic source.
Topics: Rats; Animals; Male; Rats, Wistar; Myocardium; Mitochondria, Heart; Oxidative Stress; Testosterone
PubMed: 37780627
DOI: 10.3389/fendo.2023.1206387 -
Basic Research in Cardiology Sep 2023Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present... (Review)
Review
Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.
Topics: Humans; Myocytes, Cardiac; Mitochondrial Swelling; Mitochondria; Cardiomyopathies; Myocardium; Mitochondria, Heart
PubMed: 37775647
DOI: 10.1007/s00395-023-01011-3 -
Cell Death Discovery Sep 2023The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated...
The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer's disease and we provide a candidate molecular pathway to link together such pathological events.
PubMed: 37730761
DOI: 10.1038/s41420-023-01642-4 -
JHEP Reports : Innovation in Hepatology Aug 2022In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal...
BACKGROUND & AIMS
In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging.
METHODS
To primary cocultures of astrocytes and neurons, low concentrations (1 and 5 μM) of NHCl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy.
RESULTS
Neuronal cultures treated with NHCl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both <0.0001). BDL led to increased cerebral LP ( = 0.0003) and cytosolic ROS generation ( <0.0001), which was restored by OP (both <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP.
CONCLUSIONS
Our results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development.
LAY SUMMARY
The impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.
PubMed: 35845295
DOI: 10.1016/j.jhepr.2022.100510 -
Biochemical and Biophysical Research... Sep 2023Calcium overload performs a crucial function in the pathogenesis of myocardial ischemia-reperfusion (I/R) damage, which contributes to mitochondrial impairment and...
Calcium overload performs a crucial function in the pathogenesis of myocardial ischemia-reperfusion (I/R) damage, which contributes to mitochondrial impairment and apoptosis of cardiomyocytes. Suberoylanilide hydroxamic acid (SAHA), a small molecule histone deacetylases inhibitor with modulatory capacity on Na-Ca exchanger (NCX), is proven to have protective potential towards cardiac remodeling and injury, but the mechanism remains unclear. Hence, Hence, our present research explored the modulation of NCX-Ca-CaMKII by SAHA in myocardial I/R damage. Our outcomes indicate that in vitro hypoxia and reoxygenation models of myocardial cells, SAHA treatment inhibited the increase in expression of NCX1, intracellular Ca concentration, expression of CaMKII and self-phosphorylated CaMKII, and cell apoptosis. In addition, SAHA treatment improved myocardial cell mitochondrial swelling inhibited mitochondrial membrane potential diminution and the openness of the mitochondrial permeability transition pore, and protected against mitochondrial dysfunction following I/R injury. In vivo, SAHA treatment alleviated the decrease in FS% and EF%, the increase in the myocardial infarct area, and myocardial enzyme levels caused by I/R injury, while also reducing myocardial cell apoptosis, and inhibiting mitochondrial fission and mitochondrial membrane rupture. These results indicated that SAHA treatment alleviated myocardial cell apoptosis as well as mitochondrial dysfunction resulting from myocardial I/R impairment, and contributed to myocardial function recovery by inhibiting the NCX-Ca-CaMKII pathway. These findings offered additional theoretical support to explore the mechanism of SAHA as a therapeutic agent in cardiac I/R damage and develop new treatment strategies.
Topics: Humans; Vorinostat; Histone Deacetylase Inhibitors; Myocardial Reperfusion Injury; Sodium-Calcium Exchanger; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Myocytes, Cardiac; Apoptosis
PubMed: 37300940
DOI: 10.1016/j.bbrc.2023.05.120 -
Biochimica Et Biophysica Acta.... Oct 2022Plant mitochondria are sensitive organelles affected by changing environmental stressors. Upon heat shock or the presence of reactive oxygen species, plant mitochondria... (Review)
Review
Plant mitochondria are sensitive organelles affected by changing environmental stressors. Upon heat shock or the presence of reactive oxygen species, plant mitochondria undergo in vivo morphological derangements associated with the extensively characterized opening of the mitochondrial permeability transition pore. Nevertheless, the classic mitochondrial permeability transition is known to be triggered by calcium overload causing mitochondrial swelling and dysfunction. Here we review evidence concerning calcium handling, permeability transition and mitochondrial impairments in plants, supporting the notion that the mitochondrial morphology transition is an in vivo indicator of the permeability transition.
Topics: Calcium; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Permeability
PubMed: 35772521
DOI: 10.1016/j.bbabio.2022.148586