MPTAC determines APP fragmentation via sensing sulfur amino acid catabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113609 | GEO | 2018/08/07
REPOSITORIES: GEO
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Project description:MPTAC determines APP fragmentation via sensing sulfur amino acid catabolism
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Project description:Development, growth and adult survival are coordinated with available metabolic resources. The insulin/IGF and TOR signaling pathways relay nutritional status, thereby ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21-23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is down-regulated with age. This miRNA controls branched-chain amino acid (BCAA) catabolism and the activity of the TOR kinase, a central growth regulator. Metabolite analysis suggests that the mechanistic basis may be an accumulation of BCKAs, rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g. translational fidelity. Constitutive miR-277 expression as well as transgenic inhibition with a miRNA sponge construct shortens lifespan. Furthermore, constitutive miR-277 expression is synthetically lethal with reduced insulin signaling. Thus, optimal metabolic adaptation requires tuning of cellular BCAA catabolism by miR-277 to be concordant with systemic growth signaling.
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Project description:Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway, which is the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 as a microRNA capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain and greatly reduced protein aggregates in a lentivirus model of polyglutamine disease, establishing the physiological relevance of let-7 for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond the CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms. Using sets of wild-type C57BL/6J mice, we established primary cortical neuron cultures from P0 littermates, and cultured these neurons (n = 3 / set) in CM or NLM for 4 hrs.
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Project description:Chronic kidney disease (CKD) complicates cisplatin-based chemotherapy of cancer patients. Here we investigate microRNA (miRNA)-regulated transcriptomic activity to unveil biological processes associated with cisplatin-induced kidney injury. Implementing chimeric-eCLIP-seq approach to a mouse model for cisplatin-induced CKD, we identify direct pairs of miRNA and their target messenger RNA in the injured kidney. We find a dedicated transcriptomic program directed by a group of miRNAs that alter metabolic pathways centered on mitochondria in the injured kidneys. Specifically, cisplatin-induced miRNA, miR-429-3p suppresses the mitochondria pathway that catalyzes branched-chain amino acid (BCAA), eventually leading to lipid peroxidation-dependent cell death, called ferroptosis. Thus, the identification of miRNA-429-3p-mediated stimulation of ferroptosis suggests a therapeutic potential for BCAA pathway modulation in ameliorating CKD and cisplatin-associated nephrotoxicity.
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Project description:Chronic kidney disease (CKD) complicates cisplatin-based chemotherapy of cancer patients. Here we investigate microRNA (miRNA)-regulated transcriptomic activity to unveil biological processes associated with cisplatin-induced kidney injury. Implementing chimeric-eCLIP-seq approach to a mouse model for cisplatin-induced CKD, we identify direct pairs of miRNA and their target messenger RNA in the injured kidney. We find a dedicated transcriptomic program directed by a group of miRNAs that alter metabolic pathways centered on mitochondria in the injured kidneys. Specifically, cisplatin-induced miRNA, miR-429-3p suppresses the mitochondria pathway that catalyzes branched-chain amino acid (BCAA), eventually leading to lipid peroxidation-dependent cell death, called ferroptosis. Thus, the identification of miRNA-429-3p-mediated stimulation of ferroptosis suggests a therapeutic potential for BCAA pathway modulation in ameliorating CKD and cisplatin-associated nephrotoxicity.
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Project description:Chronic kidney disease (CKD) complicates cisplatin-based chemotherapy of cancer patients. Here we investigate microRNA (miRNA)-regulated transcriptomic activity to unveil biological processes associated with cisplatin-induced kidney injury. Implementing chimeric-eCLIP-seq approach to a mouse model for cisplatin-induced CKD, we identify direct pairs of miRNA and their target messenger RNA in the injured kidney. We find a dedicated transcriptomic program directed by a group of miRNAs that alter metabolic pathways centered on mitochondria in the injured kidneys. Specifically, cisplatin-induced miRNA, miR-429-3p suppresses the mitochondria pathway that catalyzes branched-chain amino acid (BCAA), eventually leading to lipid peroxidation-dependent cell death, called ferroptosis. Thus, the identification of miRNA-429-3p-mediated stimulation of ferroptosis suggests a therapeutic potential for BCAA pathway modulation in ameliorating CKD and cisplatin-associated nephrotoxicity.
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