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Diabetic peripheral neuropathy（DPN） is a neurodegenerative disease of diabetes mellitus involving peripheral nervous system damage， which is characterized by axonal degenerative necrosis， Schwann cell apoptosis and demyelination of nerve myelin sheath as the main pathological features， this disease is highly prevalent and is a major cause of disability in diabetic patients. Currently， the pathogenesis of DPN may be related to oxidative stress， inflammatory response， metabolic abnormality， and microcirculation disorder. The treatment of DPN in modern medicine mainly starts from controlling blood glucose， nourishing nerves and improving microcirculation， which can only alleviate the clinical symptoms of patients， and it is difficult to fundamentally improve the pathological damage of peripheral nerves. Mitochondrial quality control refers to the physiological mechanisms that can maintain the morphology and functional homeostasis of mitochondria， including mitochondrial biogenesis， mitochondrial dynamics， mitochondrial oxidative stress and mitochondrial autophagy， and abnormal changes of which may cause damage to peripheral nerves. After reviewing the literature， it was found that traditional Chinese medicine（TCM） can improve the low level of mitochondrial biogenesis in DPN， maintain the balance of mitochondrial dynamics， inhibit mitochondrial oxidative stress and mitochondrial autophagy， and delay apoptosis of Schwann cells and neural axon damage， which has obvious effects on the treatment of DPN. With the deepening of research， mitochondrial quality control may become one of the potential targets for the research of new anti-DPN drugs， therefore， this paper summarized the research progress of TCM in treating DPN based on four aspects of mitochondrial quality control， with the aim of providing a theoretical research basis for the discovery of new drugs.
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With the increasing incidence of diabetes mellitus in recent years， cardiomyopathy caused by diabetes mellitus has aroused wide concern and this disease is characterized by high insidiousness and high mortality. The early pathological changes of diabetic cardiomyopathy （DCM） are mitochondrial structural disorders and loss of myocardial metabolic flexibility. The turbulence of mitochondrial quality control （MQC） is a key mechanism leading to the accumulation of damaged mitochondria and loss of myocardial metabolic flexibility， which， together with elevated levels of oxidative stress and inflammation， trigger changes in myocardial structure and function. Qi deficiency and stagnation is caused by the loss of healthy Qi， and the dysfunction of Qi transformation results in the accumulation of pathogenic Qi， which further triggers injuries. According to the theory of traditional Chinese medicine （TCM）， DCM is rooted in Qi deficiency of the heart， spleen， and kidney. The dysfunction of Qi transformation leads to the generation and lingering of turbidity， stasis， and toxin in the nutrient-blood and vessels， ultimately damaging the heart. Therefore， Qi deficiency and stagnation is the basic pathologic mechanism of DCM. Mitochondria， similar to Qi in substance and function， are one of the microscopic manifestations of Qi. The role of MQC is consistent with the defense function of Qi. In the case of MQC turbulence， mitochondrial structure and function are impaired. As a result， Qi deficiency gradually emerges and triggers pathological changes， which make it difficult to remove the stagnant pathogenic factor and aggravates the MQC turbulence. Ultimately， DCM occurs. Targeting MQC to treat DCM has become the focus of current research， and TCM has the advantages of acting on multiple targets and pathways. According to the pathogenesis of Qi deficiency and stagnation in DCM and the modern medical understanding of MQC， the treatment should follow the principles of invigorating healthy Qi， tonifying deficiency， and regulating Qi movement. This paper aims to provide ideas for formulating prescriptions and clinical references for the TCM treatment of DCM by targeting MQC.
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OBJECTIVE@#To review the research progress of mitochondrial dynamics mediated by optic atrophy 1 (OPA1) in skeletal system diseases.@*METHODS@#The literatures about OPA1-mediated mitochondrial dynamics in recent years were reviewed, and the bioactive ingredients and drugs for the treatment of skeletal system diseases were summarized, which provided a new idea for the treatment of osteoarthritis.@*RESULTS@#OPA1 is a key factor involved in mitochondrial dynamics and energetics and in maintaining the stability of the mitochondrial genome. Accumulating evidence indicates that OPA1-mediated mitochondrial dynamics plays an important role in the regulation of skeletal system diseases such as osteoarthritis, osteoporosis, and osteosarcoma.@*CONCLUSION@#OPA1-mediated mitochondrial dynamics provides an important theoretical basis for the prevention and treatment of skeletal system diseases.
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Humanos , GTP Fosfo-Hidrolases/genética , Dinâmica Mitocondrial , Osteoartrite , OsteoporoseRESUMO
Based on the O-GlcNAc transferase(OGT)-PTEN-induced putative kinase 1(PINK1) pathway, the mechanism of 3,4-dihydroxybenzaldehyde(DBD) on mitochondrial quality control was investigated. Middle cerebral artery occlusion/reperfusion(MCAO/R) rats were established. SD rats were randomized into sham operation group(sham), model group(MCAO/R), DBD-L group(5 mg·kg~(-1)), and DBD-H group(10 mg·kg~(-1)). After 7 days of administration(ig), MCAO/R was induced in rats except the sham group with the suture method. Twenty-four h after reperfusion, the neurological function and the percentage of cerebral infarct area were measured. Based on hematoxylin and eosin(HE) staining and Nissl staining, the pathological damage of cerebral neurons was examined. Then the ultrastructure of mitochondria was observed under the electron microscope, and the co-localization of light chain-3(LC3), sequestosome-1(SQSTM1/P62), and Beclin1 was further detected by immunofluorescence staining. It has been reported that the quality of mitochondria can be ensured by inducing mitochondrial autophagy through the OGT-PINK1 pathway. Therefore, Western blot was employed to detect the expression of OGT, mitophagy-related proteins PINK1 and E3 ubiquitin ligase(Parkin), and mitochondrial kinetic proteins dynamin-like protein 1(Drp1) and optic atrophy 1(Opa1). The results showed that MCAO/R group had neurological dysfunction, large cerebral infarct area(P<0.01), damaged morphological structure of neurons, decreased number of Nissl bodies, mitochondrial swelling, disappearance of mitochondrial cristae, decrease of cells with LC3 and Beclin1, rise of cells with P62(P<0.01), inhibited expression of OGT, PINK1, and Parkin, up-regulated expression of Drp1, and down-regulated expression of Opa1 compared with the sham group(P<0.01). However, DBD improved the behavioral deficits and mitochondrial health of MCAO/R rats, as manifested by the improved morphology and structure of neurons and mitochondria and the increased Nissl bodies. Moreover, DBD increased cells with LC3 and Beclin1 and decreased cells with P62(P<0.01). In addition, DBD promoted the expression of OGT, PINK1, Parkin, and Opa1 and inhibited the expression of Drp1, enhancing mitophagy(P<0.05, P<0.01). In conclusion, DBD can trigger PINK1/Parkin-mediated brain mitophagy through the OGT-PINK1 pathway, which plays a positive role in maintaining the health of the mitochondrial network. This may be a mitochondrial therapeutic mechanism to promote nerve cell survival and improve cerebral ischemia/reperfusion injury.
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Animais , Ratos , Ratos Sprague-Dawley , Proteína Beclina-1 , Mitocôndrias , Infarto Cerebral , Proteínas QuinasesRESUMO
Ulcerative colitis （UC）， a chronic inflammatory bowel disease with the accumulation of colorectal mucosa and submucosa， has a risk of developing into cancer. In recent years， the incidence of UC has been on the rise worldwide. However， its pathogenesis has not been fully elucidated by modern medicine， and even the remission rate of the latest drugs is lower than 50%， which seriously affects the patients' work and quality of life. Mitochondria， as the "power station" of eukaryotic cells， are involved in a variety of physiological processes such as the production of reactive oxygen species and the production of adenosine triphosphate by oxidative phosphorylation， and their dysfunction can lead to a series of diseases. Mitochondrial quality control （MQC） is an important way to maintain the stability of mitochondrial form， quantity， and quality. Studies have shown that MQC disorders characterized by low mitochondrial biogenesis， excessive mitochondrial oxidative stress， mitochondrial autophagy defects， mitochondrial dynamics disorders， and calcium regulation abnormalities are closely related to the occurrence and development of UC. Although progress has been achieved in the treatment of UC by traditional Chinese medicine （TCM） which can regulated MQC in a multi-pathway and multi-target manner in recent years， a review on the treatment of UC by TCM via the intervention in MQC remains to be carried out. Therefore， this paper summarized the TCM treatment of UC by regulating MQC， aiming to provide new ideas for the clinical treatment of UC by TCM.
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Objective:To evaluate the role of heme oxygenase-1 (HO-1) in endotoxin-induced acute lung injury (ALI) and the relationship with the regulation of mitochondrial quality control in mice.Methods:Clean-grade healthy male adult C57BL/6 mice, aged 6-8 weeks, weighing 20-25 g, were selected.HO-1 inducible gene knockout mice (HO-1 -/-) were prepared based on CRISPER/Cas9-mediated EGE system, and HO-1 gene overexpression mice (HO-1 + /+ ) were prepared by transfection of HO-1 overexpressed adenovirus vector.The mice were divided into 2 groups ( n=6 each) using a random number table method: control group (group WT, group HO-1 -/-, group HO-1 + /+ ) and endotoxin-induced ALI group (group ALI, group HO-1 -/-+ ALI, group HO-1 + /+ + ALI). Lipopolysaccharide 15 mg/kg was injected through the tail vein to develop the model of endotoxin-induced ALI, and the equal volume of normal saline was given instead in each control group.The mice were sacrificed by bloodletting at 12 h after lipopolysaccharide or normal saline administration.The lung tissues were harvested for microscopic examination of the pathological changes which were scored, for determination of GSH and GSSG contents, for observation of the ultrastructure of mitochondria (with a transmission electron microscope) and survival within 12 h, for measurement of mitochondrial membrane potential (MMP) levels, and for determination of the expression of mitochondrial quality control-related proteins mitochondrial fusion protein 2 (Mfn2) and dynamin-related protein 1 (Drp1), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitophagy marker protein PTEN-induced kinase 1 (PINK1) and E3 ubiquitin-protein ligase Parkin.The ratio of GSH/GSSG was calculated. Results:Compared with control group (group WT, group HO-1 + /+ and group HO-1 -/-), the 12-h survival rate and MMP were significantly decreased, the lung injury score was increased, GSH content and GSH/GSSG ratio were decreased, and the content of GSSG was increased in endotoxin-induced ALI groups (group ALI, group HO-1 + /+ + ALI and group HO-1 -/-+ ALI) ( P<0.05). Compared with group ALI, the 12-h survival rate and MMP were significantly decreased, the lung injury score was increased, the GSH content and GSH/GSSG ratio were decreased, the GSSG content was increased, and the expression of HO-1, Mfn2, PGC-1α, NRF1, PINK1 and Parkin was down-regulated, and Drp1 expression was up-regulated in group HO-1 -/-+ ALI, and 12-h survival rate and MMP were significantly increased, lung injury score was decreased, GSH content and GSH/GSSG ratio were increased, GSSG content was decreased, the expression of HO-1, Mfn2, PGC-1α, NRF1, PINK1 and Parkin was up-regulated, and the expression of Drp1 was down-regulated in group HO-1 + /+ + ALI ( P<0.05). Conclusions:HO-1 is involved in the process of endotoxin-induced ALI in mice, which is related to the regulation of mitochondrial quality control.
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Diabetic cardiomyopathy occurs in diabetic patients and is different from hypertensive heart disease， coronary atherosclerotic heart disease， and other cardiac abnormalities. The main clinical symptoms are systolic and diastolic cardiac dysfunction， myocardial fibrosis， congestive heart failure， and angina pectoris. As one of the main complications of diabetes， its incidence and fatality rates have been on the rise year by year. However， modern medicine still fails to figure out its pathogenesis and no specific drug is available， which has seriously affected the survival and quality of life of patients. Cardiomyocytes contain a large number of mitochondria， which participate in cardiac energy metabolism and other biological activities and occupy an important position in the development of diabetic cardiomyopathy. Mitochondrial quality control mainly involves mitochondrial oxidative stress， mitochondrial dynamics， mitochondrial autophagy， and intracellular calcium regulation， which is an important condition for stabilizing the normal mitochondrial structure and exerting normal mitochondrial functions. In recent years， the efficacy of traditional Chinese medicine in intervening in mitochondrial quality control through multiple angles， pathways， and targets to affect the structure and function of myocardial mitochondria and significantly improve the clinical symptoms of patients with diabetic cardiomyopathy has attracted wide attention from scholars. Therefore， this paper reviewed the experimental studies and/or clinical observations concerning the treatment of diabetic cardiomyopathy with effective compounds of Chinese herbs and/or Chinese herbal compounds in the past ten years to further explain the pathogenesis of diabetic cardiomyopathy， clarify the regulatory mechanism of traditional Chinese medicine in mitochondrial quality control， and summarize the scientific connotations and shortcomings of traditional Chinese medicine in the treatment of diabetic cardiomyopathy， hoping to provide certain ideas and methods for further clinical application of traditional Chinese medicine in the treatment of diabetic cardiomyopathy.
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The prevalence of obesity has been rising in recent years. Obesity has become one of the global public health problems‚ which can increase the risk of hypertension‚ coronary heart disease and other cardiovascular diseases‚ and prevention and treatment of obesity has become an urgent social problem to be solved. Beige adipocytes are new kind of heat-producing adipocytes‚ which can be transformed by white adipocytes stimulated by chronic cold exposure‚ some medicine and exercise. The morphology and function of beige adipocytes are different from white adipocytes‚ but are similar to brown adipocytes. Beige adipocytes have abundant mitochondria and can produce heat to consumer energy‚ which are new target for the prevention and treatment of obesity. Mitochondria is the main part of energy metabolism in eukaryotic cells‚ which can provide energy to the body. Mitochondrial quality control regulates mitochondrial quantity and quality in beige adipocytes‚ which can affect the conversion and thermogenesis of beige adipocytes. Mitochondrial quality control is regulated by several coordinated mechanisms including mitochondrial biogenesis‚ mitophagy and fission / fusion. The mitochondrial biogenesis and mitophagy can regulate mitochondrial renewal and degradation‚ and the mitochondrial fusion / division is responsible for mitochondrial repairing. Some studies have found that the change of mitochondrial quantity‚ morphology and function can affect the beige adipocytes formation‚ beige adipocytes maintenance and thermogenesis. However‚ the relationship between mitochondrial quality control and beige adipocytes remains unclear. In this review‚ we discuss the effect of mitochondrial biogenesis‚mitophagy and mitochondrial fission / fusion on beige adipocytes‚ and illustrate the relationship between mitochondrial quality control and beige adipocytes‚ which may provide new insights into the prevention and treatment of obesity.
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Mitochondria are very complex dual membrane organelles in eukaryotic cells. Under physiological conditions, the regeneration and degradation of mitochondria are balanced. When the components of the proteins, lipids and DNA in the organelles are damaged, the steady state of the mitochondria is maintained by means of division, fusion, autophagy and the like, so as to maintain the integrity of the mitochondrial structure and function, which is commonly referred to as a "mitochondrial mass control". Mitochondrial-derived vesicle (MDV) is a newly discovered pathway of mitochondrial quality control, which plays an important role in the early stage of cell stress and helps maintain the stability of mitochondrial function. In this paper, the discovery of MDV, the transport pathway, the choice of goods and the physiological effects on cells are reviewed.
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Sarcopenia is a process in which skeletal muscle mass and strength are gradually declining, resulting a main health challenge for the old adults. Mitochondria can maintain the integrity of structure and function of skeletal muscle by improving biosynthesis, antioxidant defense, fusion/fission dynamics and mitophagy. Mitochondrial dysfunction is a important factor leading to the complex etiology of sarcopenia. Exercise can regulate mitochondrial quality control pathways by activating mitochondrial biogenesis and mitophagy to maintain optimal mitochondrial function, thereby delaying and preventing the onset and progression of sarcopenia.
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Despite considerable efforts to prevent and treat cardiovascular disease (CVD), it has become the leading cause of death worldwide. Cardiac mitochondria are crucial cell organelles responsible for creating energy-rich ATP and mitochondrial dysfunction is the root cause for developing heart failure. Therefore, maintenance of mitochondrial quality control (MQC) is an essential process for cardiovascular homeostasis and cardiac health. In this review, we describe the major mechanisms of MQC system, such as mitochondrial unfolded protein response and mitophagy. Moreover, we describe the results of MQC failure in cardiac mitochondria. Furthermore, we discuss the prospects of 2 drug candidates, urolithin A and spermidine, for restoring mitochondrial homeostasis to treat CVD.
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Trifosfato de Adenosina , Doenças Cardiovasculares , Causas de Morte , Insuficiência Cardíaca , Coração , Homeostase , Mitocôndrias , Mitofagia , Organelas , Controle de Qualidade , Espermidina , Resposta a Proteínas não DobradasRESUMO
Adipose tissue inflammation is considered a major contributing factor in the development of obesity-associated insulin resistance and cardiovascular diseases. However, the cause of adipose tissue inflammation is presently unclear. The role of mitochondria in white adipocytes has long been neglected because of their low abundance. However, recent evidence suggests that mitochondria are essential for maintaining metabolic homeostasis in white adipocytes. In a series of recent studies, we found that mitochondrial function in white adipocytes is essential to the synthesis of adiponectin, which is the most abundant adipokine synthesized from adipocytes, with many favorable effects on metabolism, including improvement of insulin sensitivity and reduction of atherosclerotic processes and systemic inflammation. From these results, we propose a new hypothesis that mitochondrial dysfunction in adipocytes is a primary cause of adipose tissue inflammation and compared this hypothesis with a prevailing concept that “adipose tissue hypoxia” may underlie adipose tissue dysfunction in obesity. Recent studies have emphasized the role of the mitochondrial quality control mechanism in maintaining mitochondrial function. Future studies are warranted to test whether an inadequate mitochondrial quality control mechanism is responsible for mitochondrial dysfunction in adipocytes and adipose tissue inflammation.
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11-beta-Hidroxiesteroide Desidrogenases , Adipócitos , Adipócitos Brancos , Adipocinas , Adiponectina , Tecido Adiposo , Hipóxia , Doenças Cardiovasculares , Homeostase , Inflamação , Resistência à Insulina , Metabolismo , Mitocôndrias , Óxido Nítrico , Obesidade , Controle de QualidadeRESUMO
Objective To investigate the regulation effects of orientin on mitochondrial quality control in cardiomyocytes of rats with myocardial ischemia/reperfusion injury (MIRI). Methods A total of 75 Sprague-Dawley male rats were randomly divided into five groups: sham group, model group, and orientin preconditioning groups (1.0, 2.0, and 4.0 mg/kg). Except for sham group, all rats were exposed to modeling of MIRI with ligation of left anterior descending coronary artery (LADCA) for 30 min, and then releasing for 120 min. Mitochondrial membrane potential (MMP) and opening of mitochondrial permeability transition pore (mPTP) were detected by Microplate Reader; Activity of mitochondrial respiratory chain complexes I-IV was detected by Spectrophotometer; Cardiomyocyte apoptosis was detected by TUNEL method; Apoptosis and mitophagy related proteins were detected by Western Blot and the interaction between Parkin and p62 on mitochondria were detected by Co-IP. Results Orientin significantly restored MMP, mPTP opening threshold and activity of mitochondrial respiratory chain complexes I-IV, and reduced cardiomyocyte apoptosis. Additionally, orientin can dramatically inhibit the protein expression level apoptosis and mitophagy related proteins and weaken the interaction between Parkin and p62. Conclusion Orientin has a significant protective effect on cardiomyocyte mitochondria in MIRI rats. Its underlying mechanism is related to inhibition of hyperactivity of mitophagy in cardiomyocytes via Parkin-dependent and Parkin-independent signaling pathways.
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Mitochondrial quality control is the important mecha-nism that regulates the morphology,quantity and quality of mito-chondrial in cell to maintain cellular homeostasis and thus,cell survival and health.It has been revealed that members of Bcl-2 family are linked to mitochondrial function and integrity.Bcl-2 family proteins are the key regulators of mitochondrial quality control,participating in the signaling pathways regulating the crosstalk between mitophagy and apoptosis,as well as mitochon-drial fission and fusion.This paper mainly reviews their impact on mitochondrial quality and the major signaling pathways regula-ted by Bcl-2 family proteins.