BACKGROUND Intestinal ischemia reperfusion(I/R)occurs in various diseases,such as trauma and intestinal transplantation.Excessive reactive oxygen species(ROS)accumulation and subsequent apoptotic cell death in intesti...BACKGROUND Intestinal ischemia reperfusion(I/R)occurs in various diseases,such as trauma and intestinal transplantation.Excessive reactive oxygen species(ROS)accumulation and subsequent apoptotic cell death in intestinal epithelia are important causes of I/R injury.PTEN-induced putative kinase 1(PINK1)and phosphorylation of dynamin-related protein 1(DRP1)are critical regulators of ROS and apoptosis.However,the correlation of PINK1 and DRP1 and their function in intestinal I/R injury have not been investigated.Thus,examining the PINK1/DRP1 pathway may help to identify a protective strategy and improve the patient prognosis.AIM To clarify the mechanism of the PINK1/DRP1 pathway in intestinal I/R injury.METHODS Male C57BL/6 mice were used to generate an intestinal I/R model via superior mesenteric artery occlusion followed by reperfusion.Chiu’s score was used to evaluate intestinal mucosa damage.The mitochondrial fission inhibitor mdivi-1 was administered by intraperitoneal injection.Caco-2 cells were incubated in vitro in hypoxia/reoxygenation conditions.Small interfering RNAs and overexpression plasmids were transfected to regulate PINK1 expression.The protein expression levels of PINK1,DRP1,p-DRP1 and cleaved caspase 3 were measured by Western blotting.Cell viability was evaluated using a Cell Counting Kit-8 assay and cell apoptosis was analyzed by TUNEL staining.Mitochondrial fission and ROS were tested by MitoTracker and MitoSOX respectively.RESULTS Intestinal I/R and Caco-2 cell hypoxia/reoxygenation decreased the expression of PINK1 and p-DRP1 Ser637.Pretreatment with mdivi-1 inhibited mitochondrial fission,ROS generation,and apoptosis and ameliorated cell injury in intestinal I/R.Upon PINK1 knockdown or overexpression in vitro,we found that p-DRP1 Ser637 expression and DRP1 recruitment to the mitochondria were associated with PINK1.Furthermore,we verified the physical combination of PINK1 and p-DRP1 Ser637.CONCLUSION PINK1 is correlated with mitochondrial fission and apoptosis by regulating DRP1 phosphorylation in intestinal I/R.These results suggest that the PINK1/DRP1 pathway is involved in intestinal I/R injury,and provide a new approach for prevention and treatment.展开更多
Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury(MIRI).Moderate mitophagy can remove damaged mitochondria,inhibit excessive reactive oxygen species a...Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury(MIRI).Moderate mitophagy can remove damaged mitochondria,inhibit excessive reactive oxygen species accumulation,and protect mitochondria from damage.However,excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival,and aggravates cell death.How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane,which mainly include phosphatase and tensin homolog deleted on chromosome ten(PTEN)-induced kinase 1/Parkin,hypoxia-inducible factor-1α/Bcl-2 and adenovirus e1b19k Da interacting protein 3,FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on.In this review,the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI,and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine,thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.展开更多
Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-d...Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.展开更多
Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the P...Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.展开更多
基金the National Natural Science Foundation of China,No.81679154,No.81871547.
文摘BACKGROUND Intestinal ischemia reperfusion(I/R)occurs in various diseases,such as trauma and intestinal transplantation.Excessive reactive oxygen species(ROS)accumulation and subsequent apoptotic cell death in intestinal epithelia are important causes of I/R injury.PTEN-induced putative kinase 1(PINK1)and phosphorylation of dynamin-related protein 1(DRP1)are critical regulators of ROS and apoptosis.However,the correlation of PINK1 and DRP1 and their function in intestinal I/R injury have not been investigated.Thus,examining the PINK1/DRP1 pathway may help to identify a protective strategy and improve the patient prognosis.AIM To clarify the mechanism of the PINK1/DRP1 pathway in intestinal I/R injury.METHODS Male C57BL/6 mice were used to generate an intestinal I/R model via superior mesenteric artery occlusion followed by reperfusion.Chiu’s score was used to evaluate intestinal mucosa damage.The mitochondrial fission inhibitor mdivi-1 was administered by intraperitoneal injection.Caco-2 cells were incubated in vitro in hypoxia/reoxygenation conditions.Small interfering RNAs and overexpression plasmids were transfected to regulate PINK1 expression.The protein expression levels of PINK1,DRP1,p-DRP1 and cleaved caspase 3 were measured by Western blotting.Cell viability was evaluated using a Cell Counting Kit-8 assay and cell apoptosis was analyzed by TUNEL staining.Mitochondrial fission and ROS were tested by MitoTracker and MitoSOX respectively.RESULTS Intestinal I/R and Caco-2 cell hypoxia/reoxygenation decreased the expression of PINK1 and p-DRP1 Ser637.Pretreatment with mdivi-1 inhibited mitochondrial fission,ROS generation,and apoptosis and ameliorated cell injury in intestinal I/R.Upon PINK1 knockdown or overexpression in vitro,we found that p-DRP1 Ser637 expression and DRP1 recruitment to the mitochondria were associated with PINK1.Furthermore,we verified the physical combination of PINK1 and p-DRP1 Ser637.CONCLUSION PINK1 is correlated with mitochondrial fission and apoptosis by regulating DRP1 phosphorylation in intestinal I/R.These results suggest that the PINK1/DRP1 pathway is involved in intestinal I/R injury,and provide a new approach for prevention and treatment.
基金Supported by the Beijing University of Chinese Medicine Research and Innovation Team Project(No.2019-JYB-TD-08)Youth Science Fund Project of National Natural Science Foundation of China(No.81803906)。
文摘Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury(MIRI).Moderate mitophagy can remove damaged mitochondria,inhibit excessive reactive oxygen species accumulation,and protect mitochondria from damage.However,excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival,and aggravates cell death.How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane,which mainly include phosphatase and tensin homolog deleted on chromosome ten(PTEN)-induced kinase 1/Parkin,hypoxia-inducible factor-1α/Bcl-2 and adenovirus e1b19k Da interacting protein 3,FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on.In this review,the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI,and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine,thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.
基金funded by National Natural Science Foundation of China(81973402)Natural Science Foundation of Zhejiang Province(LYY22H310009)+1 种基金Hospital Pharmacy Scientific Research Funding Project of Zhejiang Pharmaceutical Association(2020ZYY10)Clinical research fund project of Zhejiang Medical Association(2020ZYC-A07).
文摘Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.
基金This work was supported by the National Natural Science Foundation of China(81622005)Beijing Natural Science Foundation(7172213).
文摘Clinical practice has shown that Parkin is the major causative gene found in an autosomal recessive juvenile parkin-sonism(AR-JP)via Parkin mutations and that the Parkin protein is the core expression product of the Parkin gene,which itself belongs to an E3 ubiquitin ligase.Since the discovery of the Parkin gene in the late 1990s,researchers in many countries have begun extensive research on this gene and found that in addition to AR-JP,the Parkin gene is associated with many diseases,including type 2 diabetes,leprosy,Alzheimer’s,autism,and cancer.Recent studies have found that the loss or dysfunction of Parkin has a certain relationship with tumorigenesis.In general,the Parkin gene,a well-established tumor suppressor,is deficient and mutated in a variety of malignancies.Parkin overexpres-sion inhibits tumor cell growth and promotes apoptosis.However,the functions of Parkin in tumorigenesis and its regulatory mechanisms are still not fully understood.This article describes the structure,functions,and post-transla-tional modifications of Parkin,and summarizes the recent advances in the tumor suppressive function of Parkin and its underlying mechanisms.
