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Acta Neuropathologica Communications Jun 2023Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are...
Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria. Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons. We generated large scale 2D scanning transmission electron microscopy images ('nanotomy') of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution. We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury.
Topics: Humans; Multiple Sclerosis; White Matter; Cross-Sectional Studies; Axons; Multiple Sclerosis, Chronic Progressive; Myelin Sheath; Brain
PubMed: 37340488
DOI: 10.1186/s40478-023-01598-7 -
Frontiers in Pharmacology 2022Skeletal muscles are organs with high energy requirements, especially during vigorous exercise. Adequate mitochondrial function is essential to meet the high energy...
Skeletal muscles are organs with high energy requirements, especially during vigorous exercise. Adequate mitochondrial function is essential to meet the high energy needs of skeletal muscle cells. Recent studies have reported that red ginseng can significantly improve chronic fatigue; however, the specific mechanism of action is still not clear. A chronic fatigue syndrome mouse model was developed using C57BL/6J mice through long-term compound stimulation of stress factors. Following this, the animals were orally administered 200, 400, or 600 mg/kg red ginseng extracts for 28 days. Skeletal muscle lactate acid, serum lactate dehydrogenase, urea concentrations, ATP level, mitochondrial membrane potential, activities of Na-K-ATPase and cytochrome c oxidase were determined using assay kits or an automatic biochemical analyser detection system. Skeletal muscle mitochondria morphology was observed using electron microscopy and the expression of p-AMPK, PGC-1α, ACO2 and complex I in skeletal muscle protein was determined by western blotting. Oral administration of 400 or 600 mg/kg red ginseng extract in mice with chronic fatigue reduced lactic acid, lactate dehydrogenase and urea, rescued the density and morphology of skeletal muscle mitochondria, increased the activities of Na-K-ATPase and cytochrome c oxidase, and activated the AMPK/PGC-1α cascade pathway, resulting in improved skeletal muscle mitochondrial function by restoring ATP level, mitochondrial membrane potential, complex I and mitochondrial biogenesis. The anti-fatigue effects of red ginseng are partly related to its potent mitochondrial improving activity, including decreasing mitochondrial swelling and mitochondrial membrane permeability, increasing mitochondrial biogenesis, thus ameliorating mitochondrial dysfunction.
PubMed: 36618917
DOI: 10.3389/fphar.2022.1077249 -
International Journal of Molecular... Feb 2023Cisplatin, a widely used anticancer agent, can cause nephrotoxicity, including both acute kidney injury (AKI) and chronic kidney diseases, by accumulating in renal...
Cisplatin, a widely used anticancer agent, can cause nephrotoxicity, including both acute kidney injury (AKI) and chronic kidney diseases, by accumulating in renal tubular epithelial cells (TECs). Mitochondrial pathology plays an important role in the pathogenesis of AKI. Based on the regulatory role of transcription factor EB (TFEB) in mitochondria, we investigated whether TFEB is involved in cisplatin-induced TEC damage. The results show that the expression of TFEB decreased in a concentration-dependent manner in both mouse kidney tissue and HK-2 cells when treated with cisplatin. A knockdown of TFEB aggravated cisplatin-induced renal TEC injury, which was partially reversed by TFEB overexpression in HK-2 cells. It was further observed that the TFEB knockdown also exacerbated cisplatin-induced mitochondrial damage in vitro, and included the depolarization of membrane potential, mitochondrial fragmentation and swelling, and the production of reactive oxygen species. In contrast, TFEB overexpression alleviated cisplatin-induced mitochondrial damage in TECs. These findings suggest that decreased TFEB expression may be a key mechanism of mitochondrial dysfunction in cisplatin-induced AKI, and that upregulation of TFEB has the potential to act as a therapeutic target to alleviate mitochondrial dysfunction and cisplatin-induced TEC injury. This study is important for developing therapeutic strategies to manipulate mitochondria through TFEB to delay AKI progression.
Topics: Mice; Animals; Cisplatin; Apoptosis; Acute Kidney Injury; Mitochondria; Transcription Factors; Mice, Inbred C57BL
PubMed: 36769347
DOI: 10.3390/ijms24033028 -
International Journal of Experimental... Dec 2023This study aimed to investigate the effects of mitochondrial homeostasis on lipopolysaccharide (LPS)-induced endothelial cell barrier function and the mechanisms that...
This study aimed to investigate the effects of mitochondrial homeostasis on lipopolysaccharide (LPS)-induced endothelial cell barrier function and the mechanisms that underlie these effects. Cells were treated with LPS or oligomycin (mitochondrial adenosine triphosphate synthase inhibitor) and the mitochondrial morphology, mitochondrial reactive oxygen species (mtROS), and mitochondrial membrane potential (ΔΨm) were evaluated. Moreover, the shedding of glycocalyx-heparan sulphate (HS), the levels of HS-specific degrading enzyme heparanase (HPA), and the expression of occludin and zonula occludens (ZO-1) of Tight Junctions (TJ)s, which are mediated by myosin light chain phosphorylation (p-MLC), were assessed. Examining the changes in mitochondrial homeostasis showed that adding heparinase III, which is an exogenous HPA, can destroy the integrity of glycocalyx. LPS simultaneously increased mitochondrial swelling, mtROS, and ΔΨm. Without oligomycin effects, HS, HPA levels, and p-MLC were found to be elevated, and the destruction of occludin and ZO-1 increased. Heparinase III not only damaged the glycocalyx by increasing HS shedding but also increased mitochondrial swelling and mtROS and decreased ΔΨm. Mitochondrial homeostasis is involved in LPS-induced endothelial cell barrier dysfunction by aggravating HPA and p-MLC levels. In turn, the integrated glycocalyx protects mitochondrial homeostasis.
Topics: Lipopolysaccharides; Occludin; Endothelial Cells; Tight Junctions; Oligomycins
PubMed: 37828780
DOI: 10.1111/iep.12495 -
International Journal of Molecular... Feb 2021Acute myocardial infarction is the leading cause of cardiovascular‑related mortality and chronic heart failure worldwide. As regards treatment, the reperfusion of... (Review)
Review
Acute myocardial infarction is the leading cause of cardiovascular‑related mortality and chronic heart failure worldwide. As regards treatment, the reperfusion of ischemic tissue generates irreversible damage to the myocardium, which is termed 'cardiac ischemia‑reperfusion (IR) injury'. Due to the large number of mitochondria in cardiomyocytes, an increasing number of studies have focused on the roles of mitochondria in IR injury. The primary causes of IR injury are reduced oxidative phosphorylation during hypoxia and the increased production of reactive oxygen species (ROS), together with the insufficient elimination of these oxidative species following reperfusion. IR injury includes the oxidation of DNA, incorrect modifications of proteins, the disruption of the mitochondrial membrane and respiratory chain, the loss of mitochondrial membrane potential (∆Ψm), Ca2+ overload, mitochondrial permeability transition pore formation, swelling of the mitochondria, and ultimately, cardiomyocyte necrosis. The present review article discusses the molecular mechanisms of IR injury, and summarizes the metabolic and dynamic changes occurring in the mitochondria in response to IR stress. The mitochondria are strongly recommended as a target for the development of therapeutic agents; however, the appropriate use of agents remains a challenge.
Topics: DNA, Mitochondrial; Humans; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Oxidative Stress
PubMed: 33416090
DOI: 10.3892/ijmm.2020.4823 -
Acta Medica Lituanica 2022Leber hereditary ptic neuropathy (LHON) is a disease of young adults with bilateral, painless, subacute visual loss. The peak age of onset of LHON is in the second and... (Review)
Review
Leber hereditary ptic neuropathy (LHON) is a disease of young adults with bilateral, painless, subacute visual loss. The peak age of onset of LHON is in the second and third decades of life. Men are 4 times more likely to be affected than women. In about 25-50% of cases, both eyes are affected simultaneously. In unilateral cases, the other eye is usually affected 2 to 3 months later. Visual acuity deteriorates to counting fingers or worse with a dense central or centrocecal scotoma. In the subacute phase, the optic disc may appear hyperemic with swelling of the peripapillary retinal nerve fibre layer, peripapillary telangiectasias, and increased vascular tortuosity. Ocular coherence tomography of the macula shows marked thinning of the ganglion cell complex even at this stage. The diagnosis of LHON is made in a subject with a consistent clinical history and/or one of three common pathogenic mitochondrial DNA (mtDNA) variants identified by molecular genetic testing. Idebenone was approved by the European Medicines Agency under exceptional circumstances for the treatment of LHON. Current evidence suggests some benefit to vision in a subset of affected individuals treated with idebenone, particularly when treated within the first year of onset of vision loss. In this article, we discuss aetiology, clinical features, diagnosis, differential dignosis, prognosis and treatment.
PubMed: 36061944
DOI: 10.15388/Amed.2022.29.1.19 -
International Journal of Molecular... Sep 2023This review analyzes the causes and consequences of apoptosis resulting from oxidative stress that occurs in mitochondria and cells exposed to the toxic effects of... (Review)
Review
This review analyzes the causes and consequences of apoptosis resulting from oxidative stress that occurs in mitochondria and cells exposed to the toxic effects of different-valence heavy metals (Ag, Tl, Hg, Cd, Pb, Al, Ga, In, As, Sb, Cr, and U). The problems of the relationship between the integration of these toxic metals into molecular mechanisms with the subsequent development of pathophysiological processes and the appearance of diseases caused by the accumulation of these metals in the body are also addressed in this review. Such apoptosis is characterized by a reduction in cell viability, the activation of caspase-3 and caspase-9, the expression of pro-apoptotic genes ( and ), and the activation of protein kinases (ERK, JNK, p53, and p38) by mitogens. Moreover, the oxidative stress manifests as the mitochondrial permeability transition pore (MPTP) opening, mitochondrial swelling, an increase in the production of reactive oxygen species (ROS) and HO, lipid peroxidation, cytochrome c release, a decline in the inner mitochondrial membrane potential (ΔΨ), a decrease in ATP synthesis, and reduced glutathione and oxygen consumption as well as cytoplasm and matrix calcium overload due to Ca release from the endoplasmic reticulum (ER). The apoptosis and respiratory dysfunction induced by these metals are discussed regarding their interaction with cellular and mitochondrial thiol groups and Fe metabolism disturbance. Similarities and differences in the toxic effects of Tl from those of other heavy metals under review are discussed. Similarities may be due to the increase in the cytoplasmic calcium concentration induced by Tl and these metals. One difference discussed is the failure to decrease Tl toxicity through metallothionein-dependent mechanisms. Another difference could be the decrease in reduced glutathione in the matrix due to the reversible oxidation of Tl to Tl near the centers of ROS generation in the respiratory chain. The latter may explain why thallium toxicity to humans turned out to be higher than the toxicity of mercury, lead, cadmium, copper, and zinc.
Topics: Humans; Reactive Oxygen Species; Calcium; Hydrogen Peroxide; Mitochondrial Membrane Transport Proteins; Mitochondria; Apoptosis; Oxidative Stress; Cadmium; Glutathione; Metals, Heavy; Membrane Potential, Mitochondrial
PubMed: 37833908
DOI: 10.3390/ijms241914459 -
Frontiers in Pharmacology 2021Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are...
Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-β/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-β treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentially suppression of TGF-β/Smad2 and MAPK pathways.
PubMed: 34630088
DOI: 10.3389/fphar.2021.713572 -
Journal of Hazardous Materials Jun 2022A comparative analysis of toxicities of both arsenic forms (arsenite and arsenate) in the model eukaryotic microorganism Tetrahymena thermophila (ciliate protozoa) has...
A comparative analysis of toxicities of both arsenic forms (arsenite and arsenate) in the model eukaryotic microorganism Tetrahymena thermophila (ciliate protozoa) has shown the presence of various detoxification mechanisms and cellular effects comparable to those of animal cells under arsenic stress. In the wild type strain SB1969 arsenate is almost 2.5 times more toxic than arsenite. According to the concentration addition model used in binary metallic mixtures their toxicities show an additive effect. Using fluorescent assays and flow cytometry, it has been detected that As(V) generates elevated levels of ROS/RNS compared to As(III). Both produce the same levels of superoxide anion, but As(V) also causes greater increases in hydrogen peroxide and peroxynitrite. The mitochondrial membrane potential is affected by both As(V) and As(III), and electron microscopy has also revealed that mitochondria are the main target of both arsenic ionic forms. Fusion/fission and swelling mitochondrial and mitophagy, together with macroautophagy, vacuolization and mucocyst extruction are mainly associated to As(V) toxicity, while As(III) induces an extensive lipid metabolism dysfunction (adipotropic effect). Quantitative RT-PCR analysis of some genes encoding antioxidant proteins or enzymes has shown that glutathione and thioredoxin metabolisms are involved in the response to arsenic stress. Likewise, the function of metallothioneins seems to be crucial in arsenic detoxification processes, after using both metallothionein knockout and knockdown strains and cells overexpressing metallothionein genes from this ciliate. The analysis of the differential toxicity of As(III) and As(V) shown in this study provides cytological and molecular tools to be used as biomarkers for each of the two arsenic ionic forms.
Topics: Animals; Arsenates; Arsenic; Arsenites; Metallothionein; Tetrahymena thermophila
PubMed: 35248958
DOI: 10.1016/j.jhazmat.2022.128532 -
Journal of Oncology 2022Photodynamic therapy (PDT) can be developed into an important arsenal against cancer; it is a minimally invasive therapy, which is used in the treatment or/and... (Review)
Review
Photodynamic therapy (PDT) can be developed into an important arsenal against cancer; it is a minimally invasive therapy, which is used in the treatment or/and palliation of a variety of cancers and benign diseases. The removal of cancerous tissue is achieved with the use of photosensitizer and a light source, which excites the photosensitizer. This excitation causes the photosensitizer to generate singlet oxygen and other reactive oxygen species. PDT has been used in several types of cancers including nonmelanoma skin cancer, bladder cancer, esophageal cancer, head and neck cancer, and non-small cell lung cancer (NSCLC). Although it is routinely used in nonmelanoma skin cancer, it has not been widely adopted in other solid cancers due to a lack of clinical data showing the superiority of PDT over other forms of treatment. Singlet oxygen used in PDT can alter the activity of the catalase, which induces immunomodulation through HOCl signaling. The singlet oxygen can induce apoptosis through both the extrinsic and intrinsic pathways. The extrinsic pathway of apoptosis starts with the activation of the Fas receptor by singlet oxygen that leads to activation of the caspase-7 and caspase-3. In the case of the intrinsic pathway, disruption caused by singlet oxygen in the mitochondria membrane leads to the release of cytochrome c, which binds with APAF-1 and procaspase-9, forming a complex, which activates caspase-3. Mechanisms of PDT action can vary according to organelles affected. In the plasma membrane, membrane disruption is caused by the oxidative stress leading to the intake of calcium ions, which causes swelling and rupture of cells due to excess intake of water, whereas disruption of lysosome causes the release of the cathepsins B and D, which cleave Bid into tBid, which changes the mitochondrial outer membrane permeability (MOMP). Oxidative stress causes misfolding of protein in the endoplasmic reticulum. When misfolding exceeds the threshold, it triggers unfolding protein response (UPR), which leads to activation of caspase-9 and caspase-3. Finally, the activation of p38 MAPK works as an alternative pathway for the induction of MOMP.
PubMed: 35794980
DOI: 10.1155/2022/7211485