IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis
Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R de...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/2/158 |
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| author | Susana Cardoso Icíar P. López Sergio Piñeiro-Hermida José G. Pichel Paula I. Moreira |
| author_facet | Susana Cardoso Icíar P. López Sergio Piñeiro-Hermida José G. Pichel Paula I. Moreira |
| author_sort | Susana Cardoso |
| collection | DOAJ |
| description | Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old <i>UBC-CreERT2</i>; <i>Igf1r<sup>fl/fl</sup></i> male mice in which <i>Igf1r</i> was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3β and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H<sub>2</sub>O<sub>2</sub> levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis. |
| first_indexed | 2024-03-09T05:22:17Z |
| format | Article |
| id | doaj.art-84a1c691874c4ff0adbca7b20d893917 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T05:22:17Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-84a1c691874c4ff0adbca7b20d8939172023-12-03T12:39:44ZengMDPI AGBiomedicines2227-90592021-02-019215810.3390/biomedicines9020158IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox HomeostasisSusana Cardoso0Icíar P. López1Sergio Piñeiro-Hermida2José G. Pichel3Paula I. Moreira4CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004–504 Coimbra, PortugalLung Cancer and Respiratory Diseases Unit (CIBIR), Fundación Rioja Salud, 26006 Logroño, SpainTelomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029 Madrid, SpainLung Cancer and Respiratory Diseases Unit (CIBIR), Fundación Rioja Salud, 26006 Logroño, SpainCNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004–504 Coimbra, PortugalInsulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old <i>UBC-CreERT2</i>; <i>Igf1r<sup>fl/fl</sup></i> male mice in which <i>Igf1r</i> was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR/PI3K/Akt and inhibition of the MAPK/ERK1/2/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3β and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H<sub>2</sub>O<sub>2</sub> levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis.https://www.mdpi.com/2227-9059/9/2/158braininsulin-like growth factor type 1 receptorIGF1R-mediated signalingmitochondriaredox balance<i>UBC-CreERT2</i> |
| spellingShingle | Susana Cardoso Icíar P. López Sergio Piñeiro-Hermida José G. Pichel Paula I. Moreira IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis Biomedicines brain insulin-like growth factor type 1 receptor IGF1R-mediated signaling mitochondria redox balance <i>UBC-CreERT2</i> |
| title | IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis |
| title_full | IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis |
| title_fullStr | IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis |
| title_full_unstemmed | IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis |
| title_short | IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis |
| title_sort | igf1r deficiency modulates brain signaling pathways and disturbs mitochondria and redox homeostasis |
| topic | brain insulin-like growth factor type 1 receptor IGF1R-mediated signaling mitochondria redox balance <i>UBC-CreERT2</i> |
| url | https://www.mdpi.com/2227-9059/9/2/158 |
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