Iron is an essential metal cofactor for enzymes involved in many cellular functions, such as energy generation and cell proliferation. However, excessive iron concentration leads to increased oxidative stress and toxicity. As such, iron homeostasis is strictly controlled by two RNA binding proteins known as Iron Regulatory Proteins (IRPs) that regulate the expression of iron management genes at post-transcriptional level. Despite this fine regulation, an impairment of iron homeostasis occurs during aging: iron progressively accumulates in several organs and, in turn, it exacerbates cellular vulnerability and tissue damage. Moreover, excessive iron accumulation within the CNS is observed in many neurodegenerative diseases. I investigated the age-dependent changes of iron homeostasis using the short lived fish Nothobranchius furzeri. Here, I show that: i) both iron content and expression of microRNA family miR-29 increase during adult life and aging in the N. furzeri brain; ii) iron up-regulates miR-29 expression in fish brain and murine neurons, while, in turn, miR-29 targets the 3’-UTR of IREB2 mRNA, reducing iron intake; iii) Transgenic fish with knock-down of miR-29 show significant adult-onset up- regulation of IRP2 and its target TFR1 in neurons and display enhanced age-dependent accumulation of brain iron; iv) miR-29 triggers a global gene expression response that partially overlaps with that induced by aging. My studies indicate that miR-29 modulates intracellular iron homeostasis and is up-regulated as an adaptive response to limit excessive iron accumulation and to contrast aging-induced processes.

MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging / Ripa, Roberto; relatore: Cellerino, Alessandro; Scuola Normale Superiore, 20-Sep-2016.

MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging

Ripa, Roberto
2016

Abstract

Iron is an essential metal cofactor for enzymes involved in many cellular functions, such as energy generation and cell proliferation. However, excessive iron concentration leads to increased oxidative stress and toxicity. As such, iron homeostasis is strictly controlled by two RNA binding proteins known as Iron Regulatory Proteins (IRPs) that regulate the expression of iron management genes at post-transcriptional level. Despite this fine regulation, an impairment of iron homeostasis occurs during aging: iron progressively accumulates in several organs and, in turn, it exacerbates cellular vulnerability and tissue damage. Moreover, excessive iron accumulation within the CNS is observed in many neurodegenerative diseases. I investigated the age-dependent changes of iron homeostasis using the short lived fish Nothobranchius furzeri. Here, I show that: i) both iron content and expression of microRNA family miR-29 increase during adult life and aging in the N. furzeri brain; ii) iron up-regulates miR-29 expression in fish brain and murine neurons, while, in turn, miR-29 targets the 3’-UTR of IREB2 mRNA, reducing iron intake; iii) Transgenic fish with knock-down of miR-29 show significant adult-onset up- regulation of IRP2 and its target TFR1 in neurons and display enhanced age-dependent accumulation of brain iron; iv) miR-29 triggers a global gene expression response that partially overlaps with that induced by aging. My studies indicate that miR-29 modulates intracellular iron homeostasis and is up-regulated as an adaptive response to limit excessive iron accumulation and to contrast aging-induced processes.
20-set-2016
BIO/12 BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA
Scienze biologiche
aging. iron homeostasis
Biology
cell
iron. cellular functions
Iron Regulatory Proteins (IRPs)
microRNA family miR-29
neurobiology
RNA binding proteins
Scuola Normale Superiore
Cellerino, Alessandro
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Descrizione: doctoral thesis full text
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11384/86003
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