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1.
Article in English | WPRIM | ID: wpr-786079

ABSTRACT

In type 2 diabetes (T2D), the leading cause of death is cardiovascular complications. One mechanism contributing to cardiac pathogenesis is alterations in metabolism, with the diabetic heart exhibiting increased fatty acid oxidation and reduced glucose utilisation. The processes classically thought to underlie this metabolic shift include the Randle cycle and changes to gene expression. More recently, alternative mechanisms have been proposed, most notably, changes in post-translational modification of mitochondrial proteins in the heart. This increased understanding of how metabolism is altered in the diabetic heart has highlighted new therapeutic targets, with an aim to improve cardiac function in T2D. This review focuses on metabolism in the healthy heart and how this is modified in T2D, providing evidence for the mechanisms underlying this shift. There will be emphasis on the current treatments for the heart in diabetes, alongside efforts for metabocentric pharmacological therapies.


Subject(s)
Cause of Death , Gene Expression , Glucose , Heart , Metabolism , Mitochondrial Proteins , Protein Processing, Post-Translational
2.
Acta Physiologica Sinica ; (6): 631-642, 2020.
Article in Chinese | WPRIM | ID: wpr-878208

ABSTRACT

The aim of the present study was to investigate the effects of exercises with different durations and intensities on mitochondrial autophagy and FUNDC1 in rat skeletal muscles. Sixty male Sprague-Dawley rats were randomly divided into 2- and 4-week control groups (Con), moderate-intensity exercise groups (M-ex groups, treadmill exercise, 16 m/min, 1 h/d, 6 d/week), and high-intensity exercise groups (Hi-ex groups, treadmill exercise, 35 m/min, 20 min/d, 6 d/week). The bilateral soleus muscles were separated after the intervention, and paraffin sections were prepared for transmission electron microscopy. ELISA method was used to detect the content of citrate synthase (CS). The co-localizations of microtubule-associated protein 1 light chain 3 (LC3)/cytochrome c oxidase IV (COX-IV), FUNDC1/COX-IV and LC3/FUNDC1 were observed by immunofluorescent staining in frozen sections. The skeletal muscle mitochondria were extracted, and the expression of autophagy-related proteins, including AMPKα, p-AMPKα, Unc-51 like kinase 1 (ULK1), FUNDC1, LC3 and p62, were detected by Western blot. The results showed that exercise increased mitochondrial function, i.e. peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), COX-I protein expression levels and CS content. There was no difference of mitochondrial function parameters between 2-week M-ex and 2-week Hi-ex groups, while mitochondrial function of 4-weeks Hi-ex group was significantly lower than that of 4-week M-ex group. Under the same exercise intensity, mitochondrial autophagy activation in skeletal muscle of 4-week exercise was higher than that in 2-week exercise group; Under the same duration of exercise, mitochondrial autophagy activation of Hi-ex group was higher than that in M-ex group. Both 2- and 4-week exercise intervention increased LC3/COX-IV, COX-IV/FUNDC1, and FUNDC1/LC3 co-localizations. Exercise increased LC3-II/LC3-I ratio, down-regulated p62 protein expression level, up-regulated FUNDC1, ULK1 protein expression levels and AMPKα phosphorylation, and the changes of these proteins in 4-week Hi-ex group were significantly greater than those in 4-week M-ex group. These results suggest exercise induces mitochondrial autophagy in skeletal muscles, and the activity of autophagy is related to the duration and intensity of exercise. The induction mechanism of exercise may involve the mediation of FUNDC1 expression through AMPK-ULK1 pathway.


Subject(s)
Animals , Autophagy , Exercise Therapy , Humans , Male , Membrane Proteins/physiology , Mitochondria , Mitochondrial Proteins/physiology , Muscle, Skeletal/metabolism , Rats , Rats, Sprague-Dawley
3.
Acta Physiologica Sinica ; (6): 249-254, 2020.
Article in Chinese | WPRIM | ID: wpr-827062

ABSTRACT

The aim of this study was to investigate the effect of edaravone (Eda) on the balance of mitochondrial fusion and fission in Parkinson's disease (PD) cell model. A cell model of PD was established by treating PC12 cells with 500 μmol/L 1-methyl-4-phenylpyridinium (MPP). Thiazole blue colorimetry (MTT) was used to detect the effect of different concentrations of Eda on the survival rate of PC12 cells exposed to MPP. The mitochondrial morphology was determined by laser confocal microscope. Western blot was used to measure the protein expression levels of mitochondrial fusion- and fission-related proteins, including OPA1, MFN2, DRP1 and Fis1. The results showed that pretreatment with different concentrations of Eda antagonized MPP-induced PC12 cell damage in a dose-dependent manner. The PC12 cells treated with MPP showed mitochondrial fragmentation, up-regulated DRP1 and Fis1 protein expression levels, and down-regulated MFN2 and OPA1 protein expression levels. Eda could reverse the above changes in the MPP-treated PC12 cells, but did not affect Fis1 protein expression. These results suggest that Eda has a protective effect on the mitochondrial fusion disruption induced by MPP in PC12 cells. The mechanism may be related to the up-regulation of OPA1/MFN2 and down-regulation of DRP1.


Subject(s)
1-Methyl-4-phenylpyridinium , Animals , Dynamins , Edaravone , Pharmacology , GTP Phosphohydrolases , Mitochondria , Mitochondrial Dynamics , Mitochondrial Proteins , PC12 Cells , Parkinson Disease , Rats , Up-Regulation
4.
Acta Physiologica Sinica ; (6): 475-487, 2020.
Article in Chinese | WPRIM | ID: wpr-827039

ABSTRACT

The abnormality of mitochondrial morphology and function is closely related to the pathogenesis of many diseases. Mitochondrial fusion-fission dynamics are critical to maintain normal morphology, distribution and quantity of mitochondria, and ensure the normal activity of cells. In addition, mitochondrial autophagy (mitophagy) plays an important role in maintaining mitochondrial quality by degrading aging or damaged mitochondria. Many previous studies showed that mitochondrial dynamics and mitophagy can regulate each other to sustain mitochondrial network homeostasis. Clarifying regulatory mechanisms of mitochondrial dynamics and mitophagy is of great significance for revealing the molecular mechanism of various diseases and for the development of new drugs targeting mitochondrial dynamics proteins or mitophagy regulatory proteins. This review focuses on the role of mitochondrial dynamics and mitophagy in mitochondrial quality control, regulatory mechanism, the interplay between those two processes, and their roles in human-related diseases.


Subject(s)
Autophagy , Humans , Mitochondria , Mitochondrial Dynamics , Mitochondrial Proteins , Mitophagy
5.
Article in Chinese | WPRIM | ID: wpr-772049

ABSTRACT

OBJECTIVE@#To investigate whether autophagy mediates the effects of aldehyde dehydrogenase 2 (ALDH2) on the proliferation of neonatal rat cardiac fibroblasts cultured in high glucose.@*METHODS@#Cardiac fibroblasts were isolated from neonatal (within 3 days) SD rats and subcultured. The fibroblasts of the third passage, after identification with immunofluorescence staining for vimentin, were treated with 5.5 mmol/L glucose (control group), 30 mmol/L glucose (high glucose group), or 30 mmol/L glucose in the presence of Alda-1 (an ALDH2 agonist), daidzin (an ALDH2 2 inhibitor), or both. Western blotting was employed to detect ALDH2, microtubule-associated protein 1 light chain 3B subunit (LC3B) and Beclin-1 in the cells, and a hydroxyproline detection kit was used for determining hydroxyproline content in cell culture medium; CCK- 8 kit was used for assessing the proliferation ability of the cardiac fibroblasts after the treatments.@*RESULTS@#Compared with the control cells, the cells exposed to high glucose exhibited obviously decreased expressions of ALDH2, Beclin-1 and LC3B and increased cell number and hydroxyproline content in the culture medium. Treatment of the high glucose-exposed cells with Alda-1 significantly increased Beclin-1, LC3B, and ALDH2 protein expressions and lowered the cell number and intracellular hydroxyproline content, whereas the application of daidzin resulted in reverse changes in the expressions of ALDH2, Beclin-1 and LC3B, viable cell number and intracellular hydroxyproline content in high glucose-exposed cells.@*CONCLUSIONS@#Mitochondrial ALDH2 inhibits the proliferation of neonatal rat cardiac fibroblasts induced by high glucose, and the effect is possibly mediated by the up-regulation of autophagy-related proteins Beclin-1 and LC3B.


Subject(s)
Aldehyde Dehydrogenase , Aldehyde Dehydrogenase, Mitochondrial , Metabolism , Animals , Animals, Newborn , Autophagy , Beclin-1 , Physiology , Fibroblasts , Glucose , Microtubule-Associated Proteins , Mitochondrial Proteins , Rats , Rats, Sprague-Dawley
6.
Chinese Journal of Biotechnology ; (12): 1382-1390, 2019.
Article in Chinese | WPRIM | ID: wpr-771791

ABSTRACT

Mitochondrial dynamics, the processes of mitochondrial fusion and fission maintain homeostasis, are precisely regulated by fusion/fission-related proteins, and play an important physiological role in mitochondrial metabolism, quality and function. The aberrant changes of these proteins can trigger mitochondrial dynamics imbalance, which cause mitochondrial dysfunctions and result various disease states. This article focuses on gene knockout technology, and reviews the role and application progress of genes encoding for fusion and fission knockout mice in insulin resistance researches, in order to lay a foundation for future studies on signal transduction mechanism of mitochondrial dynamics imbalance in insulin resistance.


Subject(s)
Animals , Gene Knockout Techniques , Insulin Resistance , Mice , Mitochondria , Mitochondrial Dynamics , Mitochondrial Proteins
7.
Acta Physiologica Sinica ; (6): 625-636, 2019.
Article in Chinese | WPRIM | ID: wpr-777148

ABSTRACT

Mitochondrial dynamics, involving mitochondrial fusion, fission and autophagy, plays an important role in maintaining cellular physiological function and homeostasis. Mitochondria are the "energy plant" of human body, so the changes of mitochondrial fusion, division and autophagy are important for cell respiration and energy production. On the other hand, energy metabolism influences mitochondrial dynamics in turn. This paper reviewed the recent advances in studies on the relationship between energy metabolism and the proteins regulating mitochondrial fusion, fission and autophagy. The association of mitochondrial dynamics with electron chain complex expression, oxidative phosphorylation and ATP synthesis upon exercise intervention will provide theoretical references for the further studies in sports training and disease intervention.


Subject(s)
Adenosine Triphosphate , Autophagy , Energy Metabolism , Exercise , Humans , Mitochondria , Physiology , Mitochondrial Dynamics , Mitochondrial Proteins , Metabolism
8.
Article in Chinese | WPRIM | ID: wpr-775049

ABSTRACT

This article reports the clinical features and C12orf65 gene mutations of a girl with autosomal recessive spastic paraplegia-55. The 8-year-old girl experienced disease onset at the age of 5 years and had optic atrophy as the main clinical manifestation, with slow movements in standing up and a slight duck-shaped gait. Peripheral blood DNA samples were collected from this child and her parents and brother to perform high-throughput whole-exome sequencing and high-throughput mitochondrial genome sequencing. Sanger sequencing was performed for verification. The results showed two compound heterozygous mutations, c.394C>T and c.447_449delGGAinsGT, in the C12orf65 gene. The former mutation came from her father and was a known pathogenic mutation, and the latter came from her mother and was a novel mutation which had not been reported in literature. This study expands the mutation spectrum of the C12orf65 gene and thus provides a molecular basis for the etiological diagnosis of the child and the genetic counseling of the family.


Subject(s)
Child , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Mitochondrial Proteins , Genetics , Mutation , Pedigree , Peptide Termination Factors , Genetics , Spastic Paraplegia, Hereditary , Genetics
9.
Article in English | WPRIM | ID: wpr-765654

ABSTRACT

Diabetes mellitus increases the risk for the development of heart failure even in the absence of coronary artery disease and hypertension, a cardiac entity termed diabetic cardiomyopathy (DC). Clinically, DC is increasingly recognized and typically characterized by concentric cardiac hypertrophy and diastolic dysfunction, ultimately resulting in heart failure with preserved ejection fraction (HFpEF) and potentially even heart failure with reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie the alterations in myocardial structure and function in DC, many of which show similar alterations in the failing heart. Well investigated and established mechanisms of DC include increased myocardial fibrosis, enhanced apoptosis, oxidative stress, impaired intracellular calcium handling, substrate metabolic alterations, and inflammation, among others. In addition, a number of novel mechanisms that receive increasing attention have been identified in recent years, including autophagy, dysregulation of microRNAs, epigenetic mechanisms, and alterations in mitochondrial protein acetylation, dynamics and quality control. This review aims to provide an overview and update of established underlying mechanisms of DC, as well as a discussion of recently identified and emerging mechanisms that may also contribute to the structural and functional alterations in DC.


Subject(s)
Acetylation , Apoptosis , Autophagy , Calcium , Cardiomegaly , Coronary Artery Disease , Diabetes Mellitus , Diabetic Cardiomyopathies , Epigenomics , Fibrosis , Heart , Heart Failure , Hypertension , Inflammation , MicroRNAs , Mitochondrial Proteins , Oxidative Stress , Quality Control
10.
Article in English | WPRIM | ID: wpr-763045

ABSTRACT

Niacinamide (NIA) is a water-soluble vitamin that is widely used in the treatment of skin diseases. Moreover, NIA displays antioxidant effects and helps repair damaged DNA. Recent studies showed that particulate matter 2.5 (PM(2.5)) induced reactive oxygen species (ROS), causing disruption of DNA, lipids, and protein, mitochondrial depolarization, and apoptosis of skin keratinocytes. Here, we investigated the protective effects of NIA on PM(2.5)-induced oxidative stress in human HaCaT keratinocytes. We found that NIA could inhibit the ROS generation induced by PM(2.5), as well block the PM(2.5)-induced oxidation of molecules, such as lipids, proteins, and DNA. Furthermore, NIA alleviated PM(2.5)-induced accumulation of cellular Ca²⁺, which caused cell membrane depolarization and apoptosis, and reduced the number of apoptotic cells. Collectively, the findings show that NIA can protect keratinocytes from PM(2.5)-induced oxidative stress and cell damage.


Subject(s)
Antioxidants , Apoptosis , Cell Membrane , DNA , Humans , Keratinocytes , Mitochondrial Proteins , Niacinamide , Oxidative Stress , Particulate Matter , Reactive Oxygen Species , Skin Diseases , Skin , Vitamins
11.
Chonnam Medical Journal ; : 136-143, 2019.
Article in English | WPRIM | ID: wpr-763292

ABSTRACT

Today, the incidence of cancer in the world is rising, and it is expected that in the next several decades, the number of people suffering from cancer or (the cancer rate) will double. Cancer is defined as the excessive and uncontrolled growth of cells; of course (in simple terms), cancer is considered to be a set of other diseases that ultimately causes normal cells to be transformed into neoplastic cells. One of the most important causes of the onset and exacerbation of cancer is excessive oxidative stress. One of the most important proteins in the inner membrane of mitochondria is Reactive Oxygen Species (ROS) Modulator 1 (ROMO1) that interferes with the production of ROS, and with increasing the rate of this protein, oxidative stress will increase, which ultimately leads to some diseases, especially cancer. In this overview, we use some global databases to provide information about ROMO1 cellular signaling pathways, their related proteins and molecules, and some of the diseases associated with the mitochondrial protein, especially cancer.


Subject(s)
Diagnosis , Incidence , Membranes , Mitochondria , Mitochondrial Proteins , Oxidative Stress , Reactive Oxygen Species
12.
Acta cir. bras ; 33(2): 117-124, Feb. 2018. tab, graf
Article in English | LILACS | ID: biblio-886260

ABSTRACT

Abstract Purpose: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). Methods: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B <intraperitoneally injected with 20 mg/kg (10 mg/ml) of saline before preparing the ischemia-reperfusion (IR) model>, and group C <intraperitoneally injected with 20 mg/kg (10 mg/ml) of PCr immediately before preparing the IR model>. After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. Results: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. Conclusions: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.


Subject(s)
Humans , Animals , Male , Rats , Phosphocreatine/pharmacology , Cardiotonic Agents/pharmacology , Reperfusion Injury/metabolism , Brain Ischemia/metabolism , Mitochondrial Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , X-Linked Inhibitor of Apoptosis Protein/metabolism , Random Allocation , Brain Ischemia/prevention & control , Rats, Sprague-Dawley , Apoptosis/drug effects , Neuroprotective Agents/pharmacology , Disease Models, Animal , Drug Evaluation, Preclinical , Apoptosis Regulatory Proteins , Caspase 3/metabolism
13.
Article in Chinese | WPRIM | ID: wpr-776579

ABSTRACT

OBJECTIVE@#To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms.@*METHODS@#Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 μg/kg) in each group after two days, once every other day.On 18 day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed.@*RESULTS@#Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (<0.01).@*CONCLUSIONS@#Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.


Subject(s)
Animals , Apoptosis , Carcinoma, Hepatocellular , Cell Line, Tumor , Dipeptides , Humans , Indoles , Liver Neoplasms , Male , Mice , Mice, Inbred BALB C , Mitochondrial Proteins
14.
São Paulo; s.n; s.n; 2018. 112 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-967941

ABSTRACT

A ausência de XPC, uma proteína canonicamente envolvida em reparo de DNA por excisão de nucleotídeos, está associada a vários fenótipos característicos de disfunção mitocondrial como o desequilíbrio entre os complexos da cadeia transportadora de elétrons (CTE), redução no consumo de oxigênio, maior produção de peróxido de hidrogênio, e maior sensibilidade a agentes que causam estresse mitocondrial. Contudo, uma descrição mecanística da relação entre deficiência de XPC e disfunção mitocondrial ainda não está bem estabelecida. Aqui mostramos que a deficiência de XPC está associada ao aumento na expressão do supressor de tumor p53. Essa alteração é acompanhada pelo aumento da expressão de diversas proteínas que participam em importantes funções mitocondriais. A inibição de p53 reverte a superexpressão de algumas dessas proteínas. O tratamento com o inibidor do Complexo III da CTE antimicina A induz aumento da expressão de p53 de forma mais acentuada na linhagem Xpc-/-, enquanto o tratamento com o antioxidante N-acetilcisteína diminue a produção basal de H2O2, expressão de p53 e sensibilidade aumentada ao tratamento com antimicina A. Em conjunto, nossos resultados suportam a hipótese de que o aumento da produção de H2O2 em células Xpc-/- tem um papel causal na regulação da expressão de p53 e na disfunção mitocondrial


Although XPC has been initially implicated in the nucleotide excision DNA repair pathway, its deficiency is associated with mitochondrial dysfunction, including unbalanced electron transport chain (ETC) activity, lower oxygen consumption, increased hydrogen peroxide production, and greater sensitivity to mitochondrial stress. However, a mechanistic understanding of the role of XPC in regulating mitochondrial function is still not well established. Here we show that XPC deficiency is associated with increased expression of the tumor suppressor p53, which is accompanied by increased expression of several proteins that participate in important mitochondrial functions. Inhibition of p53 reverses the overexpression of some of these proteins. In addition, treatment with the ETC inhibitor antimycin A induces p53 expression more robustly in the Xpc-/- cells, while treatment with the antioxidant N-acetylcysteine decreases basal H2O2 production, p53 expression and sensitivity to antimycin A treatment. Together, our results support a model in which increased H2O2 production in Xpc-/- causes upregulation of p53 expression and mitochondrial dysfunction


Subject(s)
Xeroderma Pigmentosum/classification , Tumor Suppressor Protein p53/pharmacokinetics , Mitochondrial Proteins , Hydrogen Peroxide/analysis , Genes, p53/physiology , Antimycin A/adverse effects
15.
Protein & Cell ; (12): 693-716, 2018.
Article in English | WPRIM | ID: wpr-756928

ABSTRACT

Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson's disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trak1 that causes hypertonia in mice. Moreover, elevated Trak1 protein expression is associated with several types of cancers and variants in Trak1 are linked to childhood absence epilepsy in humans. Despite the importance of Trak1 in health and disease, the mechanisms of Trak1 action remain unclear and the pathogenic effects of Trak1 mutation are unknown. Here we report that Trak1 has a crucial function in regulation of mitochondrial fusion. Depletion of Trak1 inhibits mitochondrial fusion, resulting in mitochondrial fragmentation, whereas overexpression of Trak1 elongates and enlarges mitochondria. Our analyses revealed that Trak1 interacts and colocalizes with mitofusins on the outer mitochondrial membrane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trak1 is required for stress-induced mitochondrial hyperfusion and pro-survival response. We found that hypertonia-associated mutation impairs Trak1 mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trak1 as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochondrial dynamics to hypertonia pathogenesis.


Subject(s)
Adaptor Proteins, Vesicular Transport , Metabolism , Animals , HeLa Cells , Humans , Membrane Fusion , Mice , Mitochondria , Metabolism , Mitochondrial Proteins , Metabolism , Muscle Proteins , Metabolism , Tumor Cells, Cultured
16.
Oman Medical Journal. 2017; 32 (1): 66-68
in English | IMEMR | ID: emr-185728

ABSTRACT

Mutations in the C19 or f12 gene are known to cause mitochondrial membrane protein associated neurodegeneration [MPAN], which is a neurodegeneration with brain iron accumulation [NBIA] type 4 disorder. To the best of our knowledge, this is the first report of a genetically confirmed case of MPAN from Oman. A novel homozygous deletion of exon 2 of the C19 or f12 gene was confirmed on the proband, a seven-year old girl, who presented with gait instability. Brain magnetic resonance imaging showed iron deposition on the basal ganglia. This report highlights the importance of genetic testing of such a clinically and genetically heterogeneous condition among a population with a high consanguinity rate. To overcome the diagnostic difficulty, implementation of a cost-effective approach to perform cascade screening of carriers at risk is needed as well as programs to address risky consanguineous marriages


Subject(s)
Child , Female , Humans , Brain/pathology , Mitochondrial Proteins/genetics , Consanguinity , Sequence Deletion
17.
Immune Network ; : 77-88, 2017.
Article in English | WPRIM | ID: wpr-51913

ABSTRACT

Mitochondria are key organelles involved in energy production, functioning as the metabolic hubs of cells. Recent findings emphasize the emerging role of the mitochondrion as a key intracellular signaling platform regulating innate immune and inflammatory responses. Several mitochondrial proteins and mitochondrial reactive oxygen species have emerged as central players orchestrating the innate immune responses to pathogens and damaging ligands. This review explores our current understanding of the roles played by mitochondria in regulation of innate immunity and inflammatory responses. Recent advances in our understanding of the relationship between autophagy, mitochondria, and inflammasome activation are also briefly discussed. A comprehensive understanding of mitochondrial role in toll-like receptor-mediated innate immune responses and NLRP3 inflammasome complex activation, will facilitate development of novel therapeutics to treat various infectious, inflammatory, and autoimmune disorders.


Subject(s)
Autophagy , Immunity, Innate , Inflammasomes , Inflammation , Ligands , Mitochondria , Mitochondrial Proteins , Organelles , Reactive Oxygen Species
18.
Asian Spine Journal ; : 863-869, 2017.
Article in English | WPRIM | ID: wpr-102663

ABSTRACT

STUDY DESIGN: Human herniated discs were obtained from discectomy specimens for the immunohistochemical detection of O-GlcNAc and O-GlcNAcase (OGA)/O-GlcNAc transferase (OGT). PURPOSE: This study aimed to quantify the extent of O-GlcNAcylation and its associated enzymes (OGT/OGA) in human degenerated intervertebral discs. OVERVIEW OF LITERATURE: The O-GlcNAcylation of nuclear, cytoplasmic, and mitochondrial proteins as well as the effects of such post-translational modifications are currently the focus of extensive research. O-GlcNAcylation is believed to contribute to the etiology of chronic illnesses by acting as a nutrient and stress sensor in the cellular environment. Mature intervertebral disc cells are chondrocyte-like cells, and O-GlcNAc has been shown to promote chondrocyte apoptosis in vitro. We believe that O-GlcNAcylation is a key regulator of disc degeneration. METHODS: Fifty-six specimens were fixed for 24 hours in a 10% solution of neutral-buffered formaldehyde, dehydrated, and embedded in paraffin. Tissue slices (4-µm-thick) were used for hematoxylin-eosin staining and immunohistochemistry. RESULTS: We found that O-GlcNAcylation of cytoplasmic proteins was less than that of nuclear proteins in both single cells and cell clusters. Cytoplasmic O-GlcNAcylation occurs subsequent to nuclear O-GlcNAcylation and is directly proportional to disc degeneration. OGT and O-GlcNAc expression levels were identical in all specimens examined. CONCLUSIONS: O-GlcNAc and OGA/OGT expression is shown to correlate for the first time with intervertebral disc cell degeneration. Increasing disc degeneration is associated with increasing O-GlcNAcylation in both nuclear and cytoplasmic proteins in human disc cells.


Subject(s)
Apoptosis , Chondrocytes , Chronic Disease , Cytoplasm , Diskectomy , Formaldehyde , Humans , Immunohistochemistry , In Vitro Techniques , Intervertebral Disc Degeneration , Intervertebral Disc Displacement , Intervertebral Disc , Mitochondrial Proteins , Nuclear Proteins , Paraffin , Protein Processing, Post-Translational , Spine , Transferases
19.
Protein & Cell ; (12): 25-38, 2017.
Article in English | WPRIM | ID: wpr-757373

ABSTRACT

Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 (FUNDC1) was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with microtubule-associated protein light chain 3 beta (LC3B) through its LC3 interaction region (LIR). Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDC1 LIR peptide phosphorylated at Ser17 (pS), demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS. Alternatively, phosphorylated Tyr18 (pY) and Ser13 (pS) in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry (ITC) assays. Therefore, our structural and biochemical results reveal a working model for the specific recognition of FUNDC1 by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy.


Subject(s)
Crystallography, X-Ray , Membrane Proteins , Chemistry , Metabolism , Microtubule-Associated Proteins , Chemistry , Metabolism , Mitophagy , Mitochondrial Proteins , Chemistry , Metabolism , Peptides , Chemistry , Metabolism , Phosphorylation , Protein Structure, Quaternary
20.
Article in Korean | WPRIM | ID: wpr-761240

ABSTRACT

Ménière's disease is a poorly understood disorder of the inner ear characterized by intermittent episodic vertigo, fluctuating hearing loss, ear fullness and tinnitus. In this paper, we present a review of the histopathology, cytochemistry, gene, blood-labyrinthine barrier and imaging of Ménière's disease. Histopathology is significant for neuroepithelial damage with hair cell loss, basement membrane thickening, perivascular damage and microvascular damage. Cytochemical alterations are significant for altered AQP4 and AQP6 expression in the supporting cell, and altered cochlin and mitochondrial protein expression. Since the discovery of aquaporin water channels (AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7 and AQP9), it has become clear that these channels play a crucial role in inner ear fluid homeostasis. Several gene studies related to Ménière's disease have been published, but there is no clear evidence that Ménière's disease is associated with a special gene. Currently, imaging techniques to determine the extent and presence of endolymphatic hydrops are being studied, and further studies are needed to correlate the visualization of the endolymphatic hydrops with clinical symptoms.


Subject(s)
Aquaporins , Basement Membrane , Ear , Ear, Inner , Endolymphatic Hydrops , Hair , Hearing Loss , Histocytochemistry , Homeostasis , Magnetic Resonance Imaging , Meniere Disease , Mitochondrial Proteins , Tinnitus , Vertigo
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