高迁移率族蛋白1通过PINK1/Parkin介导的线粒体自噬促进骨髓干细胞的趋化及成骨分化

目的 探讨高迁移率族蛋白1（HMGB1）通过PTEN诱导假定激酶1（PINK1）/帕金蛋白(Parkin)介导的线粒体自噬对骨髓干细胞的趋化及成骨分化的影响。方法 将人骨髓间充质干细胞（hBMSCs）分为7组：control组、siRNA-NC组、siRNA-HMGB1组、pcDNA-NC组、pcDNA-HMGB1组、pcDNA-HMGB1+siRNA-NC组、pcDNA-HMGB1+siRNA-PINK1组。采用Transwell检测细胞迁移能力;茜素红染色检测各组细胞中钙结节数目;ELISA检测骨桥蛋白（OPN）、碱性磷酸酶（ALP）的含量;RT-qPCR检测各组细胞中成骨细胞特异性转录因子（Osterix）、HMGB1及Runt相关转录因子2（RUNX2）、转录因子CCAAT/增强子结合蛋白（C/EBPα）、过氧化物酶体增殖物激活受体γ（PPARγ）水平;透射电镜检测线粒体自噬小体数目;Western Blot检测hBMSCs中Parkin及微管相关蛋白1A/1B-轻链3（LC3Ⅱ/Ⅰ）、选择性自噬接头蛋白62（P62）和自噬关键分子酵母Atg6同系物（Beclin1）等线粒体自噬相关蛋白的表达。结果 HMGB1通过PINK1/Parkin介导的线粒体自噬对hBMSCs的趋化作用研究表明：与pcDNA-NC组相比,pcDNA-HMGB1组HMGB1表达、细胞迁移率、线粒体自噬数目及自噬相关蛋白Beclin-1、LC3B-Ⅱ/Ⅰ的表达增加,Parkin、P62等蛋白的表达降低（P＜0.05）;与siRNA-NC组相比,siRNA-HMGB1组HMGB1表达、细胞迁移率、线粒体自噬数目及Beclin-1、LC3B-Ⅱ/Ⅰ等表达降低,Parkin、P62表达增高（P＜0.01）。HMGB1通过PINK1/Parkin介导的线粒体自噬对hBMSCs的成骨分化作用研究结果显示：与pcDNA-NC组相比,pcDNA-HMGB1组钙结节数量、Osterix及RUNX2含量、ALP及OPN的表达升高（P＜0.01）,PPARγ、C/EBPα的表达降低（P＜0.05）;与pcDNA-HMGB1+siRNA-NC组相比,pcDNA HMGB1+siRNA-PINK1组钙结节数量、Osterix及RUNX2含量、ALP及OPN的表达降低（P＜0.05）,PPARγ、C/EBPα的表达升高（P＜0.05）。结论 HMGB1高表达能通过PINK1/Parkin介导的线粒体自噬促进hBMSCs的趋化、成骨细胞分化及抑制成脂细胞分化,可能是骨质疏松症的潜在治疗靶点。     

线粒体自噬最新研究进展

活性氧由线粒体产生且作用于线粒体.在压力环境下,选择性降解损伤的线粒体,并维持正常的线粒体数量对维持细胞的正常结构、生长起重要作用.线粒体通透性改变、过氧化氢酶失活等诸多影响因素都会促进线粒体自噬的发生.最近研究发现PINK1-Parkin信号通路,Mfn1、Mfn2和OPA1等蛋白与线粒体关系紧密,调控线粒体的融合、分裂、自噬.线粒体自噬可能导致神经退行性疾病,主要的神经退行性疾病包括帕金森病(Parkinson's disease,PD)、肌萎缩侧索硬化症(Alzheimer's disease,AD)、亨廷顿舞蹈病等(Huntington's disease,HD),这些与线粒体的动态改变有关.     

Mitophagy inhibits proliferation by decreasing cyclooxygenase-2 (COX-2) in arsenic trioxide-treated HepG2 cells

Mitochondrial damage can trigger mitophagy and eventually suppress proliferation. However, the effect of mitophagy on proliferation remains unclear. In this study, HepG2 cells were used to assess mitophagy and proliferation arrest in response to As₂O₃ exposure. The stimulatory effect of As₂O₃ on mitophagy was investigated by assessing morphology (mitophagosome and mitolysosome) and relevant proteins (PINK1, LC3 II/I, and COX IV). Additionally, the relationship of mitophagy and proliferation was explored through the use of mitophagy inhibitors (CsA, Mdivi-1). Interestingly, the inhibition of mitophagy rescued proliferation arrest by restoring COX-2 protein level and countered the elimination of mitochondria-located COX-2 and up-regulated the COX-2 mRNA level. Taken together, our findings indicated that mitophagy can be induced and can inhibit proliferation by reducing COX-2 in HepG2 cells during As₂O₃ treatment.     

Mitochondrial dynamics in Parkinson's disease

The unique energy demands of neurons require well-orchestrated distribution and maintenance of mitochondria. Thus, dynamic properties of mitochondria, including fission, fusion, trafficking, biogenesis, and degradation, are critical to all cells, but may be particularly important in neurons. Dysfunction in mitochondrial dynamics has been linked to neuropathies and is increasingly being linked to several neurodegenerative diseases, but the evidence is particularly strong, and continuously accumulating, in Parkinson's disease (PD). The unique characteristics of neurons that degenerate in PD may predispose those neuronal populations to susceptibility to alterations in mitochondrial dynamics. In addition, evidence from PD-related toxins supports that mitochondrial fission, fusion, and transport may be involved in pathogenesis. Furthermore, rapidly increasing evidence suggests that two proteins linked to familial forms of the disease, parkin and PINK1, interact in a common pathway to regulate mitochondrial fission/fusion. Parkin may also play a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Taken together, the current data suggests that mitochondrial dynamics may play a role in PD pathogenesis, and a better understanding of mitochondrial dynamics within the neuron may lead to future therapeutic treatments for PD, potentially aimed at some of the earliest pathogenic events.     

线粒体质量控制调控骨质疏松的研究机制进展

摘 要 线粒体是细胞内的信号中枢，在细胞生存、代谢和死亡过程中发挥关键作用。细胞需要维持线粒体的健康状态，并快速修复或清除受损的线粒体，以避免细胞死亡和组织损伤。线粒体质量控制（MQC）机制用于监测和维持线粒体的数量和质量，其中包括线粒体融合和裂变、线粒体生物发生和自噬等过程。骨质疏松症（OP）是一种常见的与衰老相关的疾病，其特征是骨量减少和易碎性骨折。研究发现，线粒体功能障碍在骨质疏松的发展中起着重要作用，线粒体异常功能和数量减少会导致骨细胞代谢紊乱，进而影响骨组织的结构和功能。因此，严格控制线粒体的质量和数量对于预防线粒体损伤对骨质疏松的病理影响至关重要。本综述旨在概述MQC所涉及的分子机制，总结目前MQC在骨质疏松进展中的复杂作用及潜在的治疗策略。     

Autophagy in alcohol-induced liver diseases

Alcohol is the most abused substance worldwide and a significant source of liver injury; the mechanisms of alcohol-induced liver disease are not fully understood. Significant cellular toxicity and impairment of protein synthesis and degradation occur in alcohol-exposed liver cells, along with changes in energy balance and modified responses to pathogens. Autophagy is the process of cellular catabolism through the lysosomal-dependent machinery, which maintains a balance among protein synthesis, degradation, and recycling of self. Autophagy is part of normal homeostasis and it can be triggered by multiple factors that threaten cell integrity, including starvation, toxins, or pathogens. Multiple factors regulate autophagy; survival and preservation of cellular integrity at the expense of inadequately folded proteins and damaged high-energy generating intracellular organelles are prominent targets of autophagy in pathological conditions. Coincidentally, inadequately folded proteins accumulate and high-energy generating intracellular organelles, such as mitochondria, are damaged by alcohol abuse; these alcohol-induced pathological findings prompted investigation of the role of autophagy in the pathogenesis of alcohol-induced liver damage. Our review summarizes the current knowledge about the role and implications of autophagy in alcohol-induced liver disease.     

N-乙酰半胱氨酸对非酒精性脂肪性肝炎模型小鼠肝细胞线粒体自噬的影响

目的在非酒精性脂肪性肝炎模型小鼠中探索N-乙酰半胱氨酸(NAC)对肝细胞线粒体自噬的影响。方法C57BL/J6小鼠分别给予16周的正常饮食、高脂高糖(HFCD)饮食和HFCD+NAC饮食。比较HE和Masson染色、ALT、AST、IL-1β、肝组织甘油三酯水平评价小鼠肝损伤。通过免疫荧光染色观察线粒体自噬。比较3组小鼠肝组织内线粒体自噬标志物在mRNA和蛋白水平的变化。结果HFCD组小鼠较对照组ALT[(24.9±2.12)比(176.7±44.32)U/L,P<0.05]、AST[(76.7±9.06)比(291.3±39.66)U/L,P<0.05]、IL-1β[(2.94±0.08)比(9.12±1.21),P<0.05]显著升高,HFCD+NAC组较HFCD组肝功能好转,IL-1β降低[(9.12±1.21)比(6.77±0.58)ng/L,P<0.05]。HFCD组小鼠肝组织内Parkin、PINK1表达降低,同时LC3B II/I比值降低,P62表达量增高。提示HFCD组小鼠肝细胞线粒体自噬水平降低。HFCD+NAC组较HFCD组线粒体自噬水平升高,差异有统计学意义(P<0.05)。结论NAC可能通过改善肝细胞线粒体自噬,进而减轻肝细胞炎症进展。     

Critical hubs of renal ischemia-reperfusion injury: endoplasmic reticulum-mitochondria tethering complexes

Mitochondrial injury and endoplasmic reticulum (ER) stress are considered to be the key mechanisms of renal ischemia-reperfusion (I/R) injury. Mitochondria are membrane-bound organelles that form close physical contact with a specific domain of the ER, known as mitochondrial-associated membranes. The close physical contact between them is mainly restrained by ER-mitochondria tethering complexes, which can play an important role in mitochondrial damage, ER stress, lipid homeostasis, and cell death. Several ER-mitochondria tethering complex components are involved in the process of renal I/R injury. A better understanding of the physical and functional interaction between ER and mitochondria is helpful to further clarify the mechanism of renal I/R injury and provide potential therapeutic targets. In this review, we aim to describe the structure of the tethering complex and elucidate its pivotal role in renal I/R injury by summarizing its role in many important mechanisms, such as mitophagy, mitochondrial fission, mitochondrial fusion, apoptosis and necrosis, ER stress, mitochondrial substance transport, and lipid metabolism.     

线粒体自噬在COPD发病机制中作用的研究进展

慢性阻塞性肺疾病(COPD)是最常见的呼吸系统疾病之一.自噬是内质网膜包裹并降解异常蛋白质和细胞器的细胞途径,对维持细胞正常生理功能至关重要.线粒体是细胞中最重要的细胞器,主要参与能量生成和氧化还原反应等重要细胞过程.线粒体自噬是一种选择性清除损伤线粒体的自噬过程,是维持线粒体功能和数量正常的重要途径.越来越多的研究发现,线粒体自噬在COPD的病理生理过程中发挥着重要作用,故本文将线粒体自噬在COPD发病机制中的作用进行综述.