线粒体非折叠蛋白反应对运动性骨骼肌代谢稳态的调节作用

线粒体非折叠蛋白反应(UPRmt)是一种适应性应激反应通路,在运动性骨骼肌代谢稳态中起重要作用。UPRmt在运动、组织缺氧、氧化应激、禁食、钙离子稳态失衡和肌肉收缩刺激等能量应激下,将线粒体基质积累或产生的大量未折叠或错误折叠的蛋白质,通过上调核基因编码的线粒体分子伴侣热激蛋白60(HSP60)、热激蛋白70(HSP70)的表达,帮助发生错误折叠的蛋白恢复正常蛋白构象及协助新合成的蛋白发生正确折叠,将信号从线粒体转导至细胞核,此过程有助于维持线粒体内蛋白质的动态平衡和细胞存活,从而保证线粒体蛋白组的最佳质量和功能,维持线粒体功能完整,保证骨骼肌代谢稳态。运动训练可通过UPRmt使线粒体网络结构功能重塑,也可使线粒体蛋白的质量控制稳定,进一步巩固和优化线粒体功能,维持骨骼肌质量和功能完整性,从而稳定骨骼肌代谢功能的稳态,同时还能有效防治神经退行性疾病、肌肉功能异常、肥胖和II型糖尿病等代谢疾病的发生,也为线粒体等相关疾病的病理机制及防治措施提供新的理论依据。

线粒体代谢介导的表观遗传改变与衰老研究

线粒体是细胞物质代谢与能量代谢的中心,在多种生理和病理过程中扮演着重要角色。表观遗传修饰是一种独立于DNA序列并在建立与维持特定基因表达谱中发挥主要作用的遗传调控模式。近年来的研究表明,线粒体能量代谢通过中间产物,介导线粒体–核信号的传递,调节染色质的表观修饰状态,进而影响基因表达。线粒体代谢紊乱可以诱导表观遗传重编程,进而启动衰老表型及退行性疾病的发生。本文综述了线粒体代谢与染色质表观遗传修饰关系的研究进展,探讨了线粒体应激在染色质重组中发挥的作用,展望了其在认知功能障碍等衰老相关性疾病研究中的前景。

The “mitochondrial stress responses”: the “Dr. Jekyll and Mr. Hyde” of neuronal disorders

Neuronal disorders are associated with a profound loss of mitochondrial functions caused by various stress conditions,such as oxidative and metabolic stress,protein folding or import defects,and mitochondrial DNA alteration.Cells engage in different coordinated responses to safeguard mitochondrial homeostasis.In this review,we will explore the contribution of mitochondrial stress responses that are activated by the organelle to perceive these dangerous conditions,keep them under control and rescue the physiological condition of nervous cells.In the sections to come,particular attention will be dedicated to analyzing how compensatory mitochondrial hyperfusion,mitophagy,mitochondrial unfolding protein response,and apoptosis impact human neuronal diseases.Finally,we will discuss the relevance of the new concept:the“mito-inflammation”,a mitochondria-mediated inflammatory response that is recently found to cover a relevant role in the pathogenesis of diverse inflammatory-related diseases,including neuronal disorders.

Molecular insights into the transgenerational inheritance of stress memory

There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.

脾气虚大鼠心肌细胞线粒体Lon蛋白酶和ClpXP复合物表达的研究

目的:通过研究心肌细胞线粒体L o n蛋白酶和C l p X P复合物的表达,围绕线粒体未折叠蛋白反应(UPRmt)探讨脾病及心的可能机制。方法:16只雄性SD大鼠随机分为正常组和脾气虚证模型组(模型组);鼠尾动脉无创测压法测定血压;心脏彩超检查心脏功能;透射电镜观察心肌细胞线粒体形态;ELISA法检测三磷酸腺苷(ATP)和MDA水平,Western Blot法检测心肌细胞线粒体Lon蛋白酶和ClpXP复合物的表达。结果:与正常组比较,模型组心率、收缩压、舒张压、左室射血分数和左室短轴缩短率均下降(P<0.01),线粒体内可见致密颗粒,ATP水平下降(P<0.01),MDA含量升高(P<0.01),Lon蛋白酶和ClpX表达均升高(P<0.05,P<0.01),但ClpP表达变化不明显。结论:脾病及心的现代医学机制可能与心肌细胞UPRmt未充分启动所导致的线粒体蛋白失稳态有关。