PINK1/Parkin-mediated mitophagy is an important process in selective removal of damaged mitochondria, in which translocation of Parkin to damaged mitochondria is recognized as an initiation step. At present, how the d...PINK1/Parkin-mediated mitophagy is an important process in selective removal of damaged mitochondria, in which translocation of Parkin to damaged mitochondria is recognized as an initiation step. At present, how the damaged mitochondria are selectively recognized and targeted by Parkin is not fully understood. Here we show that Miro2, an outer mitochondrial membrane protein, undergoes demultimerization from a tetramer to a monomer and alteration in mitochondrial localization upon CCCP treatment, suggesting a CCCP-induced realignment of Miro2. The realignment of Miro2 is tightly regulated by PINK1-mediated phosphorylation at Ser325/Ser430 and by Ca^2+binding to EF2 domain, which are both essential for the subsequent Parkin translocation. Interestingly, ablation of Miro2 in mouse causes delayed reticulocyte maturation, lactic acidosis and cardiac disorders. Furthermore, several Miro2 mutations found in the congenital lactic acidosis patients also disable its realignment and Parkin translocation. These findings reveal an important role of Miro2 to mediate Parkin translocation by sensing both depolarization and Ca^2+release from damaged mitochondria to ensure the accuracy of mitophagy.展开更多
Background Adult neurogenesis occurs in the subventricular zone(SVZ)and the subgranular zone of the dentate gyrus in the hippocampus.The neuronal stem cells in these two neurogenic niches respond differently to variou...Background Adult neurogenesis occurs in the subventricular zone(SVZ)and the subgranular zone of the dentate gyrus in the hippocampus.The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli.Recently,we have found that the decrement of carboxypeptidase E(CPE)with aging impairs the maturation of brain-derived neurotrophic factor(BDNF)and neurogenesis in the SVZ.However,it remains unknown whether these events occur in the hippocampus,and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease(AD).Methods In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches.Among these,two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD.We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice,using direct intracerebroventricular injection or by non-invasive intranasal instillation.Results Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis.By screening the miRNA mimics targeting the 5’UTR region of Cpe gene,we developed two agomirs that were capable of upregulating CPE expression.The two agomirs significantly rescued adult neurogenesis and cognition,showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice.Of note,noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.Conclusions CPE may regulate adult hippocampal neurogenesis via the CPE-BDNF-TrkB signaling pathway.This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging-and disease-related neurological decline in human brains.展开更多
基金supported by the National Natural Science Foundation of China (91754204)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010107)+5 种基金National Key Research and Development Program of China (2018YFA0108500, 2017YFC1001001)the National NaturalScience Foundation of China (81630078, 31670822, 31401151, 31570816, 81371415)the Natural Science Foundation of Beijing (5181001)CAS Strategic Priority Research Program (XDB14030300)the State Key Laboratory of Membrane Biologythe Key Laboratory of Genomic and Precision Medicine
文摘PINK1/Parkin-mediated mitophagy is an important process in selective removal of damaged mitochondria, in which translocation of Parkin to damaged mitochondria is recognized as an initiation step. At present, how the damaged mitochondria are selectively recognized and targeted by Parkin is not fully understood. Here we show that Miro2, an outer mitochondrial membrane protein, undergoes demultimerization from a tetramer to a monomer and alteration in mitochondrial localization upon CCCP treatment, suggesting a CCCP-induced realignment of Miro2. The realignment of Miro2 is tightly regulated by PINK1-mediated phosphorylation at Ser325/Ser430 and by Ca^2+binding to EF2 domain, which are both essential for the subsequent Parkin translocation. Interestingly, ablation of Miro2 in mouse causes delayed reticulocyte maturation, lactic acidosis and cardiac disorders. Furthermore, several Miro2 mutations found in the congenital lactic acidosis patients also disable its realignment and Parkin translocation. These findings reveal an important role of Miro2 to mediate Parkin translocation by sensing both depolarization and Ca^2+release from damaged mitochondria to ensure the accuracy of mitophagy.
基金supported by National Natural Science Foundation of China 82030033(T.-S.T.),81921006(T.-S.T.),92254301(T.-S.T.),82341006(C.G.),82330090(G.G.),32070780(H.L.),Beijing Natural Science Foundation IS23071(C.G.),and the State Key Laboratory of Membrane Biology。
文摘Background Adult neurogenesis occurs in the subventricular zone(SVZ)and the subgranular zone of the dentate gyrus in the hippocampus.The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli.Recently,we have found that the decrement of carboxypeptidase E(CPE)with aging impairs the maturation of brain-derived neurotrophic factor(BDNF)and neurogenesis in the SVZ.However,it remains unknown whether these events occur in the hippocampus,and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease(AD).Methods In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches.Among these,two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD.We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice,using direct intracerebroventricular injection or by non-invasive intranasal instillation.Results Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis.By screening the miRNA mimics targeting the 5’UTR region of Cpe gene,we developed two agomirs that were capable of upregulating CPE expression.The two agomirs significantly rescued adult neurogenesis and cognition,showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice.Of note,noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.Conclusions CPE may regulate adult hippocampal neurogenesis via the CPE-BDNF-TrkB signaling pathway.This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging-and disease-related neurological decline in human brains.
