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 alte...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.展开更多
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 environme...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.展开更多
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...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。展开更多
Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses,yet how chromatin remodeling is coordinated under stress remains unclear.Here,we uncover a phosphorylation-dependent mechanism b...Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses,yet how chromatin remodeling is coordinated under stress remains unclear.Here,we uncover a phosphorylation-dependent mechanism by which mitochondrial stress regulates the activity of the Nu RD(nucleosome remodeling and deacetylase)complex via LIN-40,the Caenorhabditis elegans homolog of mammalian MTA proteins.Mitochondrial stress triggers dephosphorylation of LIN-40,enhancing its interaction with the transcription factor DVE-1 to activate the mitochondrial unfolded protein response(UPR mt)and chromatin remodeling.Phosphorylation of LIN-40 is mediated by p38 MAPK/PMK-3 and reversed by PP1c/GSP-2.Furthermore,the LIN-40(T654D)variant abolishes mitochondrial stress-induced lifespan extension.These findings establish a direct link between mitochondrial stress signaling and chromatin remodeling via Nu RD,revealing an evolutionarily conserved strategy to coordinate cellular resilience and organismal longevity.展开更多
The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research.Despite extensive investigations into the loss of regenerative potential during evolution and development,un...The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research.Despite extensive investigations into the loss of regenerative potential during evolution and development,unlocking the mechanisms governing cardiomyocyte proliferation remains elusive.Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication,shedding light on novel factors that regu-late cardiomyocyte proliferation.The studies identified two mitochondrial processes,fatty acid oxidation and protein translation,as key players in restricting cardiomyocyte proliferation.Inhibition of these processes led to increased cell cycle activity in cardiomyocytes,mediated by reduction in H3k4me3 levels through accumulatedα-ketoglutarate(αKG),and activation of the mitochondrial unfolded protein response(UPRmt),respectively.In this research highlight,we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies,the broad implications in cardiomyocyte biology and cardiovascular diseases,as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyo-cyte metabolism,proliferation,and mitochondrial-to-nuclear communications.展开更多
基金supported by grants from local funds from University of Ferrara, FIR-2021the Italian Ministry of Health(GR-2016-02364602)+4 种基金the Italian Ministry of Education, University and Research(PRIN Grant 2017XA5 J5 N)(to AR)grants from Italian Association for Cancer Research(AIRC, IG-23670)Telethon(GGP11139 B)local funds from the University of Ferrarathe Italian Ministry of Education, University and Research(PRIN Grant 2017 E5 L5 P3)(to PP): Associazione Ricerca Oncologica Sperimentale Estense(AROSE)
文摘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.
基金supported by the National Key R&D Program of China(2017YFA0506400)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)+1 种基金the National Natural Science Foundation of China(31930023,31771333)supported by the China National Postdoctoral Program for Innovative Talents(BX2021356)。
文摘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.
文摘目的: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。
基金supported by the National Key Research and Development Program of China(2022YFA1303000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)+2 种基金the National Natural Science Foundation of China(32371214,32225025,92254305,32321004,32430025)the CAS Project for Young Scientists in Basic Research(YSBR-076)the Youth Innovation Promotion Association CAS(2021094)。
文摘Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses,yet how chromatin remodeling is coordinated under stress remains unclear.Here,we uncover a phosphorylation-dependent mechanism by which mitochondrial stress regulates the activity of the Nu RD(nucleosome remodeling and deacetylase)complex via LIN-40,the Caenorhabditis elegans homolog of mammalian MTA proteins.Mitochondrial stress triggers dephosphorylation of LIN-40,enhancing its interaction with the transcription factor DVE-1 to activate the mitochondrial unfolded protein response(UPR mt)and chromatin remodeling.Phosphorylation of LIN-40 is mediated by p38 MAPK/PMK-3 and reversed by PP1c/GSP-2.Furthermore,the LIN-40(T654D)variant abolishes mitochondrial stress-induced lifespan extension.These findings establish a direct link between mitochondrial stress signaling and chromatin remodeling via Nu RD,revealing an evolutionarily conserved strategy to coordinate cellular resilience and organismal longevity.
基金Key Research and Development Program,Ministry of Science and Technology of China(2018YFA0800104)National Natural Science Foundation of China(92168205,32070823)Fundamental Research Funds for the Central Universities(22120230471).
文摘The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research.Despite extensive investigations into the loss of regenerative potential during evolution and development,unlocking the mechanisms governing cardiomyocyte proliferation remains elusive.Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication,shedding light on novel factors that regu-late cardiomyocyte proliferation.The studies identified two mitochondrial processes,fatty acid oxidation and protein translation,as key players in restricting cardiomyocyte proliferation.Inhibition of these processes led to increased cell cycle activity in cardiomyocytes,mediated by reduction in H3k4me3 levels through accumulatedα-ketoglutarate(αKG),and activation of the mitochondrial unfolded protein response(UPRmt),respectively.In this research highlight,we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies,the broad implications in cardiomyocyte biology and cardiovascular diseases,as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyo-cyte metabolism,proliferation,and mitochondrial-to-nuclear communications.
